Modified TREM, composition and related methods

Abstract

The present invention generally relates to tRNA-based effector molecules containing a lock nucleic acid (LNA) moiety, as well as compositions and related methods. This disclosure features modified tRNA-based effector molecules (TREMs, e.g., TREM or TREM fragments), as well as related compositions and uses. As provided herein, TREMs are complex molecules capable of mediating various cellular processes. TREMs disclosed herein include, for example, nucleotides containing a lock nucleic acid moiety or a 2',5'-linked nucleotide on a component nucleotide (e.g., a nucleotide sugar).

Description

[Technical Field]

[0001] Claim of priority This application claims priority to U.S. Patent Application No. 63 / 458,793, filed on April 12, 2023, and U.S. Patent Application No. 63 / 458,885, also filed on April 12, 2023. The disclosures of each of the above applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Transfer RNA (tRNA) is a complex, naturally occurring RNA molecule that has several functions, including protein initiation and elongation. [Overview of the project] [Means for solving the problem]

[0003] This disclosure features modified tRNA-based effector molecules (TREMs, e.g., TREM or TREM fragments), as well as related compositions and uses thereof. As provided herein, TREMs are complex molecules capable of mediating various cellular processes. TREMs disclosed herein include, for example, nucleotides containing a locked nucleic acid moiety or a 2',5'-linked nucleotide on a component nucleotide (e.g., a nucleotide sugar). In one embodiment, the Specified Realm is provided which comprises the sequence of formula (A): [L1]x-[ASt domain 1]-[L2]x-[DH domain]-[L3]x-[ACH domain]-[VL domain]-[TH domain]-[L4]x-[ASt domain 2]-[L5]x, wherein [L1] and [VL domain] are independently optional; x is independently 0 or 1 each time it appears; and one or more of [L1], [ASt domain 1], [L2]-[DH domain], [L3], [ACH domain], [VL domain], [TH domain], [L4], [ASt domain 2], and [L5] comprises a nucleotide containing a locked nucleic acid moiety or a nucleotide containing a 2',5'-linked nucleotide. In some embodiments, the TREM comprises the sequence of formula (A-1): [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2], where [L1] and [VL domain] are optional independently; and one of [L1], [ASt domain 1], [L2]-[DH domain], [L3], [ACH domain], [VL domain], [TH domain], [L4], and [ASt domain 2] comprises a nucleotide containing a locked nucleic acid moiety or a 2',5'-linked nucleotide. In some embodiments, the TREM further comprises additional non-natural modifications. In some embodiments, the TREM disclosed herein further comprises at least one additional modification (e.g., a non-natural modification) on, for example, a component nucleotide (e.g., a nucleic acid base or sugar) or in an internucleotide region, for example, within the TREM backbone.

[0004] In one embodiment, TREM has the ability to: (a) (i) assist in protein synthesis, (ii) be charged by synthetase, (iii) be bound by elongation factors, (iv) introduce amino acids into peptide chains, (v) assist in elongation, or (vi) assist in initiation; (b) comprise at least X consecutive nucleotides without unnatural modifications, where X is 3, 4, 5, 6, 7, 8, 9, or greater than 10; and (c) comprise at least three (d) a nucleotide of type (e.g., A, T, C, G, or U) containing less than all of the same non-natural modification; (d) a nucleotide of type (e.g., A, T, C, G, or U) containing at least X nucleotides that do not contain the non-natural modification, where X = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80; (e) types including unnatural modifications (e.g., A, T, C, G, or U) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or (f) containing 80 or fewer nucleotides of type (e.g., A, T, C, G, or U) that does not contain unnatural modifications (e.g., A, T, C, G, or U), which are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80 or fewer nucleotides.

[0005] In certain embodiments, the TREM includes feature (a)(i). In certain embodiments, the TREM includes feature (a)(ii). In certain embodiments, the TREM includes feature (a)(iii). In certain embodiments, the TREM includes feature (a)(iv). In certain embodiments, the TREM includes feature (a)(v). In certain embodiments, the TREM includes feature (a)(vi). In certain embodiments, the TREM includes feature (b). In certain embodiments, the TREM includes feature (c). In certain embodiments, the TREM includes feature (d). In certain embodiments, the TREM includes feature (e). In certain embodiments, the TREM includes feature (f). In certain embodiments, the TREM includes all or a combination of features (a)-(f).

[0006] In certain embodiments, a TREM domain comprising a non-natural modification has a function, such as a domain function described herein.

[0007] In certain aspects, herein, the sequence of formula B: [L1] y -[ASt domain 1] x -[L2] y -[DH domain] y -[L3] y -[ACH domain] x -[VL domain] y -[TH domain] y -[L4] y -[ASt domain 2] x is a TREM core fragment comprising where x = 1 and y = 0 or 1; and one of [ASt domain 1], [ACH domain], and [ASt domain 2] comprises nucleotides having a non-natural modification, a TREM core fragment is provided.

[0008] In some embodiments, TREM has the ability to assist in protein synthesis. In some embodiments, TREM has the ability to be modulated by synthetases. In some embodiments, TREM has the ability to be bound by elongation factors. In some embodiments, TREM has the ability to introduce amino acids into peptide chains. In some embodiments, TREM has the ability to assist in elongation. In some embodiments, TREM has the ability to assist in initiation.

[0009] In one embodiment, [ASt domain 1] and / or [ASt domain 2], including non-natural modifications, have the ability to initiate or elongate polypeptide chains.

[0010] In one embodiment, the [ACH domain], including unnatural modifications, has the ability to mediate pairing with codons.

[0011] In one embodiment, y=1 for one, two, three, four, five, six, all, or any combination of [L1], [L2], [DH domain], [L3], [VL domain], [TH domain], and [L4].

[0012] In one embodiment, y=0 for one, two, three, four, five, six, all, or any combination of [L1], [L2], [DH domain], [L3], [VL domain], [TH domain], and [L4].

[0013] In one embodiment, y=1 for linker[L1], and L1 contains a nucleotide having unnatural modifications.

[0014] In one embodiment, y=1 for linker [L2], and L2 contains a nucleotide having unnatural modifications.

[0015] In one embodiment, y=1 for the [DH domain (DHD)], and the DHD contains a nucleotide with unnatural modifications. In one embodiment, the DHD containing unnatural modifications has the ability to mediate recognition by aminoacyl-tRNA synthetase.

[0016] In one embodiment, y=1 for linker[L3], and L3 contains a nucleotide having unnatural modifications.

[0017] In one embodiment, y=1 for the [VL domain (VLD)], and the VLD contains a nucleotide having a non-natural modification.

[0018] In one embodiment, y=1 for the [TH domain (THD)], and the THD contains nucleotides with unnatural modifications. In one embodiment, the THD containing unnatural modifications has the ability to mediate ribosome recognition.

[0019] In one embodiment, y=1 for linker [L4], and L4 contains a nucleotide having unnatural modifications.

[0020] In another embodiment, the present disclosure relates to a TREM fragment comprising a portion of TREM, wherein TREM is an array of formula (A-1): The TREM fragment includes [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2], and provides a TREM fragment that includes unnatural modifications.

[0021] In one embodiment, the TREM fragment includes one, two, three, or all or any combination of the following: (a) a TREM half (e.g., derived from a cleavage in the anticodon sequence, e.g., a 5' half or a 3' half); (b) a 5' fragment (e.g., derived from a cleavage in the DH domain or ACH domain, e.g., a fragment containing the 5' end); (c) a 3' fragment (e.g., derived from a cleavage in the TH domain, e.g., a fragment containing the 3' end); or (d) an internal fragment (e.g., derived from a cleavage in any one of the ACH domain, DH domain or TH domain).

[0022] In one embodiment, the TREM fragment comprises (a) a TREM half containing a nucleotide having an unnatural modification.

[0023] In one embodiment, the TREM fragment includes (b) a 5' fragment containing a nucleotide having an unnatural modification.

[0024] In one embodiment, the TREM fragment includes a 3' fragment containing a nucleotide having an unnatural modification (c).

[0025] In one embodiment, the TREM fragment includes an internal fragment comprising (d) a nucleotide having an unnatural modification.

[0026] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM domain comprises a plurality of nucleotides, each having an unnatural modification. In some embodiments, the unnatural modification includes nucleic acid base modification, sugar (e.g., ribose) modification, or skeletal modification. In some embodiments, the unnatural modification is sugar (e.g., ribose) modification. In some embodiments, the unnatural modification is 2'-ribose modification, e.g., 2'-OMe, 2'-halo (e.g., 2'-F), 2'-MOE, or 2'-deoxy modification. In some embodiments, the unnatural modification is skeletal modification, e.g., phosphorothioate modification.

[0027] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM sequence includes a CCA sequence at a terminal, e.g., the 3' terminal. In some embodiments, the TREM sequence does not include a CCA sequence at a terminal, e.g., the 3' terminal.

[0028] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the non-natural modification is a base modification selected from the modifications listed in Table 5.

[0029] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM, TREM core fragment, or TREM fragment is coded by the sequence provided in Table 1, for example, one of sequence numbers 1 to 451.

[0030] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM, TREM core fragment, or TREM fragment is coded by a consensus sequence selected from any one of sequence numbers 562 to 621.

[0031] In some embodiments of any TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM, TREM core fragment, or TREM fragment is coded by a sequence provided in Figure 1, for example, SEQ ID NOs. 625-1416, for example, SEQ ID NOs. 625-793, 794-991, or 992-1416. In some embodiments, the TREM, TREM core fragment, or TREM fragment includes a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with the TREM provided in Figure 1, for example, SEQ ID NOs. 625-1416, for example, SEQ ID NOs. 625-793, 794-991, or 992-1416. In one embodiment, the TREM, TREM core fragment, or TREM fragment comprises a sequence that differs from the TREM provided in Figure 1, for example, any one of sequence numbers 625-1416, for example, any one of sequence numbers 625-793, 794-991, or 992-1416, by only 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer nucleotides. In one embodiment, the TREM, TREM core fragment, or TREM fragment includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-natural modifications (e.g., 2'-ribose modifications or internucleotide modifications, e.g., 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothiorate modifications) compared to the TREM, TREM core fragment, or TREM fragment provided in Figure 1, e.g., any one of sequence numbers 625-1416, e.g., any one of sequence numbers 625-793, 794-991, or 992-1416. In one embodiment, the TREM, TREM core fragment, or TREM fragment contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional LNA moieties or 2',5'-linked nucleotides compared to any one of the TREM, TREM core fragment, or TREM fragments provided in Figure 1, for example, any one of SEQ ID NOs. 625-1416, for example, any one of SEQ ID NOs. 625-793, 794-991, or 992-1416.

[0032] In some embodiments of any TREM, TREM core fragment, or TREM fragment disclosed herein, the TREM, TREM core fragment, or TREM fragment is a TREM provided in Figure 1, for example, any one of TREM numbers 1 to 791, for example, any one of TREM numbers 1 to 169, 170 to 367, or 368 to 791. In some embodiments, the TREM, TREM core fragment, or TREM fragment includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-natural modifications (e.g., 2'-ribose modifications or internucleotide modifications, for example, 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothiolate modifications) compared to the TREM provided in Figure 1, for example, any one of TREM numbers 1 to 791, for example, any one of TREM numbers 1 to 169, 170 to 367, or 368 to 791.

[0033] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a TREM, a TREM core fragment, or a TREM fragment as disclosed herein.

[0034] In another embodiment, TREM or related compositions may be used, in particular, to modulate functional parameters (e.g., expression parameters and / or signaling parameters) of RNA corresponding to a nucleic acid sequence containing an endogenous open reading frame (ORF) having an immature stop codon (PTC), or of a polypeptide encoded by such a nucleic acid sequence.

[0035] In another embodiment, a method is provided herein for modulating the functional parameters of mRNA corresponding to an endogenous open reading frame (ORF) in a subject, or a polypeptide encoded by such an endogenous open reading frame (ORF), comprising contacting the subject with a TREM composition comprising a TREM, TREM core fragment, or TREM fragment (e.g., a TREM, TREM core fragment, or TREM fragment comprising an LNA moiety or a 2',5'-linked nucleotide) disclosed herein, in an amount sufficient to modulate the functional parameters of the mRNA or polypeptide, and for a sufficient amount of time, wherein the TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with a codon having a first sequence. In one embodiment, the functional parameters include, for example, signaling parameters and / or expression parameters described herein.

[0036] In another embodiment, a method for regulating the expression of a protein in a cell is disclosed herein, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) containing an immature stop codon (PTC), and the method comprises contacting a cell with a TREM, TREM core fragment, or TREM composition comprising a TREM, TREM core fragment, or TREM fragment (e.g., a TREM, TREM core fragment, or TREM fragment containing an LNA moiety or a 2',5'-linked nucleotide) in an amount and / or for a sufficient amount of time to regulate the expression of the encoded protein, thereby regulating the expression of the protein in the cell, wherein the TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with the PTC. In some embodiments, the PTC comprises UAA, UGA, or UAG.

[0037] In another embodiment, this specification provides a method for increasing the expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) comprising an immature stop codon (PTC), and the method comprises contacting the subject with a TREM composition in an amount and / or for a sufficient amount of time to increase the expression of the protein, comprising (i) an anticodon that pairs with the PTC, (ii) an aminoacyl-tRNA synthetase specific to Trp, Tyr, Cys, Glu, Lys, Gln, Ser, Leu, Arg, or Gly, and (iii) a sequence of formula A, or (iv) an unnatural modification. In some embodiments, the PTC comprises UAA, UGA, or UAG. In some embodiments, the TREM composition comprises (i). In some embodiments, the TREM composition comprises (ii). In some embodiments, the TREM composition comprises (iii). In some embodiments, the TREM composition comprises (iv). In some embodiments, the TREM composition comprises two of (i) to (iv). In one embodiment, the TREM composition comprises three of (i) to (iv). In another embodiment, the TREM composition comprises each of (i) to (iv).

[0038] In another embodiment, the Disclosure provides a method for treating a subject having an endogenous open reading frame (ORF) containing an immature stop codon (PTC), comprising providing a TREM, TREM core fragment, or TREM composition comprising a TREM comprising an anticodon that pairs with the PTC in the ORF; and providing a method comprising contacting the subject with the TREM, TREM core fragment, or composition comprising a TREM comprising an amount sufficient to treat the subject and / or for a sufficient amount of time, thereby treating the subject. In one embodiment, the PTC comprises UAA, UGA, or UAG.

[0039] In another embodiment, the Disclosure provides a method for treating a subject having a disease or disorder associated with an immature stop codon (PTC), comprising a TREM, a TREM core fragment, or a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment (e.g., a TREM, a TREM core fragment, or a TREM fragment comprising an LNA moiety or a 2',5'-linked nucleotide) as disclosed herein; and a method comprising contacting the subject with a composition comprising a TREM, a TREM core fragment, or a TREM fragment in an amount sufficient to treat the subject and / or for a sufficient amount of time, thereby treating the subject. In some embodiments, the PTC comprises UAA, UGA, or UAG. In some embodiments, the disease or disorder associated with a PTC is a disease or disorder described herein, e.g., cancer or monogenetic disorder.

[0040] In some embodiment of any of the methods disclosed herein, the codon having the first sequence includes a mutation (e.g., a point mutation, e.g., a nonsense mutation) resulting in an immature stop codon (PTC) selected from UAA, UGA, or UAG. In some embodiments, the codon having the first sequence or PTC includes a UAA mutation. In some embodiments, the codon having the first sequence or PTC includes a UGA mutation. In some embodiments, the codon having the first sequence or PTC includes a UAG mutation.

[0041] In another aspect, the present disclosure provides a method for producing a TREM, a TREM core fragment, or a TREM fragment as disclosed herein, comprising ligating a first nucleotide to a second nucleotide to form a TREM.

[0042] In some embodiments, the TREM, TREM core fragment, or TREM fragment does not exist in nature (for example, it is synthetic).

[0043] In one embodiment, TREM, TREM core fragment, or TREM fragment is prepared by cell-free solid-phase synthesis.

[0044] In another aspect, the Disclosure provides a method for regulating the intracellular tRNA pool, comprising providing a TREM, a TREM core fragment, or a TREM fragment as disclosed herein, and contacting a cell with a TREM, a TREM core fragment, or a TREM fragment to thereby regulate the intracellular tRNA pool.

[0045] In some embodiments, the Disclosure provides a method for contacting cells, tissues, or subjects with a TREM, a TREM core fragment, or a TREM fragment as disclosed herein, the method comprising contacting cells, tissues, or subjects with a TREM, a TREM core fragment, or a TREM fragment, thereby bringing cells, tissues, or subjects into contact with a TREM, a TREM core fragment, or a TREM fragment.

[0046] In another aspect, the Disclosure provides a method for delivering a TREM, TREM core fragment, or TREM fragment to a cell, tissue, or subject, comprising providing the cell, tissue, or subject, and contacting the cell, tissue, or subject with the TREM, TREM core fragment, or TREM fragment disclosed herein.

[0047] In one embodiment, the present disclosure is a method for regulating an intracellular tRNA pool comprising an endogenous open reading frame (ORF) having a codon having a first sequence, By choice, to acquire knowledge about the abundance of one or both of (i) and (ii), for example, to acquire knowledge about the relative amounts of (i) and (ii) in a cell, wherein (i) is a tRNA portion having an anticodon that pairs with a codon of an ORF having a first sequence (first tRNA portion), and (ii) is an isoacceptor tRNA portion having an anticodon that pairs with a codon other than the codon having the first sequence in the cell (second tRNA portion); The cells are brought into contact with the TREM, TREM core fragment, or TREM fragment disclosed herein in an amount and / or for a sufficient amount of time to regulate the relative amounts of the first and second tRNA portions within the cell. This includes regulating the intracellular tRNA pool, Herein, we provide a method in which the TREM, TREM core fragment, or TREM fragment has a codon having a first sequence; or an anticodon that pairs with a codon other than the codon having the first sequence.

[0048] In another aspect, the present disclosure is a method for modulating the tRNA pool in an object having an ORF containing a codon having a first sequence, To obtain, by choice, knowledge about the abundance of one or both of (i) and (ii), for example, knowledge about the relative amounts of (i) and (ii) in a subject, wherein (i) is a tRNA portion having an anticodon that pairs with a codon of an ORF having a first sequence (first tRNA portion), and (ii) is an isoacceptor tRNA portion having an anticodon that pairs with a codon other than the codon having the first sequence in the subject (second tRNA portion); The subject is brought into contact with a TREM, TREM core fragment, or TREM fragment disclosed herein in an amount and / or for a sufficient amount of time to adjust the relative amounts of the first and second tRNA portions in the subject. This includes regulating the tRNA pool in the target, Herein, we provide a method in which the TREM, TREM core fragment, or TREM fragment has a codon having a first sequence; or an anticodon that pairs with a codon other than the codon having the first sequence.

[0049] In one embodiment, the present disclosure is a method for regulating the tRNA pool in an object having an endogenous ORF containing a codon containing a synonymous mutation (synonymous mutation codon or SMC), To provide a TREM, a TREM core fragment, or a composition comprising a TREM fragment disclosed herein, wherein the TREM, TREM core fragment, or TREM fragment comprises an isoacceptor-tRNA moiety (TREM) containing an anticodon sequence that pairs with an SMC; The subject is brought into contact with the composition in an amount and / or for a sufficient amount of time to modulate the tRNA pool in the subject. This provides a method that includes regulating the tRNA pool in a target.

[0050] In another aspect, the present disclosure relates to a method for regulating an intracellular tRNA pool comprising an endogenous ORF comprising a codon comprising an SMC, To provide a TREM, a TREM core fragment, or a composition comprising a TREM fragment disclosed herein, wherein the TREM, TREM core fragment, or TREM fragment comprises an isoacceptor-tRNA moiety (TREM) containing an anticodon sequence that pairs with an SMC; Cells are brought into contact with a composition containing TREM in an amount and / or for a sufficient amount of time to regulate the intracellular tRNA pool. This provides a method that includes regulating the intracellular tRNA pool.

[0051] In one embodiment, the present disclosure is a method for regulating the expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an ORF containing a mutated codon, and the method is Cells are brought into contact with a TREM, TREM core fragment, or composition comprising a TREM fragment as disclosed herein, in an amount and / or for a sufficient amount of time to modulate the expression of the encoded protein. This includes regulating the expression of proteins within cells. Here, we provide a method in which a TREM, a TREM core fragment, or a TREM fragment has an anticodon that pairs with a codon having a mutation.

[0052] In another aspect, the Disclosure relates to a method for regulating the expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous ORF containing a mutated codon, and the method is The subject is brought into contact with a TREM, TREM core fragment, or composition comprising a TREM fragment as disclosed herein, in an amount and / or for a sufficient amount of time to modulate the expression of the encoded protein. This includes regulating protein expression in the target, Here, we provide a method in which a TREM, a TREM core fragment, or a TREM fragment has an anticodon that pairs with a codon having a mutation.

[0053] In some embodiment of any of the methods disclosed herein, the mutation in the ORF is a nonsense mutation resulting in an immature stop codon selected, for example, from UAA, UGA, or UAG. In some embodiment, the stop codon is UAA. In some embodiment, the stop codon is UGA. In some embodiment, the stop codon is UAG.

[0054] In one embodiment of any of the methods disclosed herein, the TREM includes an anticodon that pairs with a stop codon.

[0055] The TREMs of this disclosure include TREM, TREM core fragments, and TREM fragments. TREM, TREM core fragments, or TREM fragments may be modified with unnatural modifications, for example, to increase the level and / or activity (e.g., stability) of the TREM. For example, a pharmaceutical TREM composition containing TREM having unnatural modifications may be administered to cells, tissues, or subjects, for example, in vitro or in vivo, to modulate these functions. Disclosed herein are TREMs containing unnatural modifications, TREM core fragments, or TREM fragments, TREM compositions, preparations, methods for preparing TREM compositions and preparations, and methods for using them.

[0056] In one embodiment, the TREM, TREM core fragment, and TREM fragment include unnatural modifications that improve stability or enhance the activity of the TREM, TREM core fragment, or TREM fragment.

[0057] Any additional features of the aforementioned TREM, TREM core fragments, TREM fragments, TREM compositions, preparations, methods for producing TREM compositions and preparations, and methods for using TREM compositions and preparations include one or more features in the listed embodiments, figures, descriptions, examples, or claims.

[0058] Those skilled in the art will be able to recognize or confirm, by conventional experimentation alone, a number of equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be covered by the embodiments, drawings, description, examples, or claims listed below. [Brief explanation of the drawing]

[0059] [Figure 1-1] The exemplary TREMs described herein are, for example, a list of TREMs containing a locic nucleic acid (LNA) moiety or a 2',5'-linked nucleotide. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] Same as above. [Figure 1-5] Same as above. [Figure 1-6] Same as above. [Figure 1-7] Same as above. [Figure 1-8] Same as above. [Figure 1-9] Same as above. [Figure 1-10] Same as above. [Figure 1-11] Same as above. [Figure 1-12] Same as above. [Figure 1-13] Same as above. [Figure 1-14] Same as above. [Figure 1-15] Same as above. [Figure 1-16] Same as above. [Figure 1-17] Same as above. [Figure 1-18] Same as above. [Figure 1-19] Same as above. [Figure 1-20] Same as above. [Figure 1-21] Same as above. [Figure 1-22] Same as above. [Figure 1-23] Same as above. [Figure 1-24] Same as above. [Figure 1-25] Same as above. [Figure 1-26] Same as above. [Figure 1-27] Same as above. [Figure 1-28] Same as above. [Figure 1-29] Same as above. [Figure 1-30] Same as above. [Figure 1-31] Same as above. [Figure 1-32] Same as above. [Figure 1-33] Same as above. [Figure 1-34] Same as above. [Figure 1-35] Same as above. [Figure 1-36] Same as above. [Figure 1-37] Same as above. [Figure 1-38] Same as above. [Figure 1-39] Same as above. [Figure 1-40] Same as above. [Figure 1-41] Same as above. [Figure 1-42] Same as above. [Figure 1-43] Same as above. [Figure 1-44] Same as above. [Figure 1-45] Same as above. [Figure 1-46] Same as above. [Figure 1-47] Same as above. [Figure 1-48] Same as above. [Figure 1-49] Same as above. [Figure 1-50] Same as above. [Figure 1-51] Same as above. [Figure 1-52] Same as above. [Figure 1-53] Same as above. [Figure 1-54] Same as above. [Modes for carrying out the invention]

[0060] This disclosure features tRNA-system effector molecules (TREMs) comprising a nucleotide containing a LOK nucleic acid moiety or a 2',5'-linked nucleotide, as well as compositions and related uses and methods of preparation. As disclosed herein, TREMs are complex molecules capable of mediating various cellular processes. Pharmaceutical TREM compositions, e.g., TREMs comprising a LOK nucleic acid moiety or a 2',5'-linked nucleotide, may be administered to cells, tissues, or subjects to modulate these functions. Methods for modulating protein expression in a subject or cell, wherein the protein is encoded by a nucleic acid comprising a first sequence, e.g., a mutation, e.g., an endogenous open reading frame (ORF) having an immature stop codon (PTC), and methods for treating subjects having an endogenous open reading frame (ORF) having an immature stop codon (PTC) are also disclosed herein. TREMs comprising a LOK nucleic acid (LNA) moiety or a 2',5'-linked nucleotide and additional non-native modifications, methods for preparation thereof, and compositions thereof are further disclosed herein.

[0061] definition "To acquire" or "to obtain," as the terms are used herein, means to obtain ownership of a value, e.g., a numerical value, by "directly acquiring" or "indirectly acquiring" a physical entity or value. "Directly acquiring" means to obtain a value by performing a process (e.g., performing an analytical method). "Indirectly acquiring" means to receive a value from another party or source (e.g., a third-party laboratory that directly acquired the value).

[0062] "PTC-related disease or disorder," as used herein, includes, but is not limited to, a disease or disorder in which cells express or have previously expressed a polypeptide encoded by an ORF containing a PTC. In some embodiments, the PTC-related disease is selected from proliferative disorders (e.g., cancer), genetic disorders, metabolic disorders, immunological disorders, inflammatory diseases, or neurological disorders. Exemplary PTC-related diseases or disorders are provided in any one of Tables 15, 16, and 17. In some embodiments, the PTC-related disease is cancer. In some embodiments, the PTC-related disease is a monogenic disorder.

[0063] When the term "isoreceptor" is used herein, it refers to a plurality of molecules, each containing a different native anticodon sequence, and each of the plurality of molecules mediating the incorporation of the same amino acid, which is an amino acid that naturally corresponds to a plurality of anticodons.

[0064] When the term "modification" is used herein in relation to nucleotides, it refers to a modification of the chemical structure, such as a modification of the covalent bond of the nucleotide in question. The modification may be natural or unnatural. In some embodiments, the modification is unnatural. In some embodiments, the modification is natural. In some embodiments, the modification is synthetic. In some embodiments, the modification is one of the modifications shown in Table 5.

[0065] When the term is used herein, “natural nucleotide” refers to a nucleotide that does not contain any unnatural modifications. In some embodiments, it includes modifications that are present in nature.

[0066] When the term “unnatural modification” is used herein in relation to nucleotides, it means (a) a modification that a cell, e.g., a human cell, does not produce on endogenous tRNA; or (b) a modification that a cell, e.g., a human cell, may produce on endogenous tRNA, but such a modification is located at a position where it does not occur on native tRNA, e.g., the modification is in a domain, linker or arm, or in a domain, linker or arm, in the nucleotide and / or in a position where such a modification does not exist naturally. In either case, the modification is added by synthesis, e.g., in a cell-free reaction, e.g., a solid-phase or liquid-phase synthesis reaction. In some embodiments, an unnatural modification is a modification that does not exist (in identity, location or position) when the TREM sequence is expressed in mammalian cells, e.g., the HEK293 cell line. Exemplary unnatural modifications are shown in Table 5. In some embodiments, an unnatural modification includes a lock nucleic acid moiety or a 2',5'-linked nucleotide. In some embodiments, an unnatural modification includes a lock nucleic acid moiety. In one embodiment, the non-natural modification includes a 2',5'-linked nucleotide.

[0067] When the term is used herein, “unnaturally modified nucleotide” means a nucleotide that includes unnatural modifications on or to the sugar, nucleic acid base, or phosphate moiety.

[0068] When the term “nucleotide” is used herein, it refers to an entity comprising a sugar, typically a pentameric sugar; a nucleic acid base; and a phosphate linking group. In some embodiments, the nucleotides include naturally occurring nucleotides, such as those naturally present in human cells, e.g., adenine, thymine, guanine, cytosine, or uracil nucleotides.

[0069] "Immature stop codon" or "PTC," as used herein, refers to a stop codon present in an open reading frame (ORF) of DNA or mRNA. In some embodiments, the PTC is located upstream of a native stop codon in the ORF. In some embodiments, for example, a PTC located upstream of a native stop codon in an ORF results in the modulation of a functional parameter of the polypeptide encoded by the corresponding mRNA or ORF. In some embodiments, the PTC may differ from (or result from) a point mutation, such as a nonsense mutation, from the pre-mutation sequence. In some embodiments, the PTC may differ from (or result from) a genetic alteration, such as an abnormality other than a point mutation, such as a frameshift, deletion, insertion, rearrangement, inversion, translocation, duplication, or transversion, from the pre-mutation sequence. In some embodiments, the PTC results in the production of a cleaved protein that lacks native activity or is associated with a mutant, disease, or other undesirable phenotype. In some embodiments, the ORF containing the PTC is an ORF from a tumor suppressor gene. In one embodiment, the mutation that produces the PTC is a driver mutation, such as a mutation that gives tumor cells a growth advantage.

[0070] "Functional parameters" refer to expression parameters and / or signal transduction parameters. In some embodiments, functional parameters are expression parameters. Expression parameters include expression parameters of polypeptides or proteins encoded by endogenous ORFs having a first sequence or PTC; or expression parameters of RNA encoded by endogenous ORFs having a first sequence or PTC, such as messenger RNA. In some embodiments, expression parameters are (a) Protein translation; (b) Expression level (e.g., of polypeptides, proteins, or mRNA); (c) Post-translational modification of polypeptides or proteins; (d) Folding (for example, of polypeptides or proteins, or mRNA), (e) Structure (e.g., of polypeptides or proteins, or mRNA), (f) Transfer (e.g., of polypeptides or proteins), (g) Computation (e.g., of polypeptides or proteins, or mRNA), (h) Incorporation into supramolecular structures (e.g., polypeptides or proteins, or mRNA), e.g., incorporation into membranes, proteasomes, or ribosomes, (i) Incorporation into a multimer polypeptide, e.g., homodimer or heterodimer, and / or (j) Stability It may include.

[0071] In one embodiment, the functional parameter is a signal transduction parameter. The signal transduction parameter is (1) Regulation of signaling pathways, such as cellular signaling pathways, downstream or upstream of proteins encoded by endogenous ORFs having a first sequence or PTC; (2) Regulation of cell fate; (3) Regulation of ribosome occupation; (4) Regulation of protein translation; (5) mRNA stability regulation; (6) Protein folding and structural regulation; (7) Protein transduction or compartmentalization control; and / or (8) Regulation of protein stability It may include.

[0072] When used herein, “ORF having a PTC” refers to an open reading frame (ORF) containing an immature stop codon (PTC). In some embodiments, an ORF having a PTC is related to a disease or disorder associated with a PTC as described herein, for example, one of the diseases or disorders listed in any one of Tables 15, 16, and 17. In some embodiments, an ORF having a PTC is not related to a disease or disorder associated with a PTC.

[0073] Where the term is used herein, a “stop codon” refers to a sequence of three nucleotides in messenger RNA that terminates translation. For example, UAG, UAA, UGA (in RNA) and TAG, TAA, or TGA (in DNA) are stop codons. Stop codons are also known as amber (UAG), ochre (UAA), and opal (UGA).

[0074] When the term “tRNA-based effector molecule” or “TREM” is used herein, it refers to an RNA molecule having the structure or characteristics of (a) to (v) below, which may be a recombinant TREM, a synthetic TREM, or a TREM expressed from a heterologous cell. The TREMs described herein include a nucleotide having a lock nucleic acid moiety or a nucleotide having a 2',5'-linked nucleotide. Furthermore, the TREMs described herein are synthetic molecules and are prepared, for example, in cell-free reactions, e.g., solid-phase or liquid-phase synthesis reactions. The TREMs are chemically different from endogenous tRNA molecules prepared in cells, e.g., mammalian cells, e.g., human cells, in terms of modifications, e.g., primary sequence, type, or position. The TREMs may have several of the structures and functions of (a) to (v) (e.g., 2, 3, 4, 5, 6, 7, 8, 9).

[0075] In some embodiments, TREM is non-natural, as can be assessed by its structure or the method by which it is manufactured.

[0076] In one embodiment, the TREM includes one or more of the following structures or characteristics: (a') Any selected linker region of the consensus sequence provided in the “consensus sequence” interval, e.g., linker 1 region; (a) an amino acid-binding domain, e.g., an acceptor stem domain (AStD) (an AStD, for example, when present in other wild-type tRNA, contains an RNA sequence sufficient to mediate the acceptance of an amino acid, e.g., a cognate or non-cognate amino acid, and the transfer of an amino acid (AA) in polypeptide chain initiation or elongation). Typically, an AStD contains a 3'-terminal adenosine (CCA) for acceptor stem loading, which is part of synthetase recognition. In some embodiments, the AStD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring AStD, e.g., an AStD encoded by the nucleic acid in Table 1. In some embodiments, the TREM may contain a fragment or analogue of an AStD, e.g., an AStD encoded by the nucleic acid in Table 1, the fragment having AStD activity in one embodiment and not having AStD activity in another embodiment. (A person skilled in the art can appropriately determine the sequence corresponding to any of the domains, stems, loops, or other sequence features described herein that are derived from the nucleic acid-encoded sequences in Table 1. For example, a person skilled in the art can determine the sequence corresponding to the AStD derived from the nucleic acid-encoded tRNA sequence in Table 1.)

[0077] In one embodiment, AStD is either below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval, or differs from the consensus sequence in 1, 2, 5, or 10 or fewer locations; In one embodiment, AStD is formula I ZZZ The residues R1-R2-R3-R4-R5-R6-R7 and residue R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, AStD is Equation II ZZZ The residues R1-R2-R3-R4-R5-R6-R7 and residue R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, AStD is Equation III ZZZ The residues R1-R2-R3-R4-R5-R6-R7 and residue R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 It contains, and ZZZ represents one of the 20 amino acids; (a'-1) A linker containing residues R8-R9 of the consensus sequence provided in the "consensus sequence" interval, e.g., linker 2 region; (b) Dihydrouridine hairpin domain (DHD) (DHD contains an RNA sequence sufficient to act as a recognition site for aminoacyl-tRNA synthetase for amino acid loading of TREM, for example, when present in other wild-type tRNAs, mediating recognition by aminoacyl-tRNA synthetase). In embodiments, DHD mediates the stabilization of the tertiary structure of TREM. In some embodiments, DHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with naturally occurring DHD, e.g., DHD encoded by nucleic acids in Table 1. In some embodiments, TREM may contain a fragment or analogue of DHD, e.g., DHD encoded by nucleic acids in Table 1, the fragment having DHD activity in one embodiment and not having DHD activity in another embodiment.

[0078] In one embodiment, the DHD is either below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval, or differs from the consensus sequence in 1, 2, 5, or 10 or fewer locations; In one embodiment, DHD is given by formula I ZZZ residue R 10 -R 11 -R 12 -R 13 -R 14-R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 comprising -R, where ZZZ represents any one of the 20 amino acids; In certain embodiments, DHD is the residue R of formula II ZZZ of residue R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 comprising -R, where ZZZ represents any one of the 20 amino acids; In certain embodiments, DHD is the residue R of formula III ZZZ of residue R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 comprising -R, where ZZZ represents any one of the 20 amino acids; (b’ - 1) The residue R of the consensus sequence provided in the "Consensus Sequence" interval29 A linker, for example, linker 3 region; (c) An anticodon that binds to each codon in the mRNA, for example, an anticodon hairpin domain (ACHD) (ACHD contains, for example, a sequence sufficient to mediate (with or without wobbling) base pairing with the codon when present in other wild-type tRNAs, for example, an anticodon triplet; in certain embodiments, ACHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring ACHD, for example, an ACHD encoded by the nucleic acid in Table 1). In certain embodiments, TREM may include an ACHD, for example, a fragment or analog of an ACHD encoded by the nucleic acid in Table 1, where the fragment in some embodiments has ACHD activity and in other embodiments does not have ACHD activity.

[0079] In certain embodiments, ACHD is below the corresponding sequence of the consensus sequence provided in the "consensus sequence" section or differs from the consensus sequence at 1, 2, 5, or 10 locations or less. In certain embodiments, ACHD has the formula I ZZZ residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 and ZZZ represents any of the 20 amino acids; In certain embodiments, ACHD has the formula II ZZZ residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, ACHD is Equation III ZZZ The residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 It contains, and ZZZ represents one of the 20 amino acids; (d) Variable loop domain (VLD) (The VLD contains an RNA sequence sufficient to act as a recognition site for aminoacyl-tRNA synthetase for aminoacyl-tRNA loading of TREM, for example, when present in other wild-type tRNAs, mediating the recognition of aminoacyl-tRNA synthetase). In embodiments, the VLD mediates the stabilization of the tertiary structure of TREM. In some embodiments, the VLD modulates, for example, the specificity of TREM with respect to its homologous amino acids, for example, increasing it, for example, the VLD modulates the homologous adapter function of TREM. In some embodiments, the VLD has at least 75, 80, 85, 85, 90, 95, or 100% identity with naturally occurring VLDs, for example, VLDs encoded by nucleic acids in Table 1. In some embodiments, TREM may include a fragment or analogue of a VLD, for example, a VLD encoded by nucleic acids in Table 1, the fragment having VLD activity in one embodiment and not having VLD activity in another embodiment.

[0080] In one embodiment, the VLD is located below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval.

[0081] In one embodiment, the VLD is a residue of the consensus sequence provided in the "consensus sequence" interval -[R 47 ] X Including x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=18 x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271); (e) Thymine hairpin domain (THD) (THD comprises an RNA sequence sufficient to mediate ribosome recognition when present in other wild-type tRNAs, for example, to act as a recognition site for ribosomes to form a TREM-ribosome complex during translation). In some embodiments, THD has at least 75, 80, 85, 85, 90, 95, or 100% identity with naturally occurring THD, for example, THD encoded by the nucleic acids in Table 1. In some embodiments, TREM may comprise a fragment or analogue of THD, for example, THD encoded by the nucleic acids in Table 1, the fragment having THD activity in one embodiment and not having THD activity in another embodiment.

[0082] In one embodiment, the THD is either below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval, or differs from the consensus sequence in 1, 2, 5, or 10 or fewer locations; In one embodiment, THD is formula I ZZZ The residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, THD is expressed in formula II ZZZ The residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R60 -R 61 -R 62 -R 63 -R 64 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, THD is given by Equation III ZZZ The residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 It contains, and ZZZ represents one of the 20 amino acids; (e'1) The residue R of the consensus sequence provided in the "consensus sequence" interval 72 A linker that includes, for example, linker 4 region; (f) Under physiological conditions, it comprises a stem structure and one or more loop structures, e.g., one, two, or three loops. The loops may comprise domains described herein, e.g., domains selected from (a) to (e). The loops may comprise one or more domains. In some embodiments, the stem or loop structure has at least 75, 80, 85, 85, 90, 95, or 100% identity with naturally occurring stem or loop structures, e.g., stem or loop structures encoded by nucleic acids in Table 1. In some embodiments, TREM may comprise fragments or analogues of stem or loop structures, e.g., stem or loop structures encoded by nucleic acids in Table 1, wherein the fragments in one embodiment have the activity of the stem or loop structure, while in other embodiments they do not; (g) Tertiary structure, e.g., L-shaped tertiary structure; (h) Adapter function, i.e., TREM mediates the acceptance of amino acids, such as its congener amino acids, and mediates the transfer of AAs in the initiation or elongation of polypeptide chains; (i) Homogeneic adapter function (TREM mediates the acceptance and uptake of amino acids (e.g., homogeneic amino acids) that are naturally bound to the anticodon of the TREM that initiates or extends the polypeptide chain); (j) Non-homogeneic adapter function (TREM mediates the acceptance and incorporation of amino acids other than those naturally bound to the TREM anticodon (e.g., non-homogeneic amino acids) during polypeptide chain initiation or elongation); (k) Regulatory functions, such as epigenetic functions (e.g., gene silencing functions or signaling pathway regulation functions), cell fate regulation functions, mRNA stability regulation functions, protein stability regulation functions, protein transduction regulation functions, or protein compartmentalization functions; (l) Structures that enable ribosome binding; (m) Post-transcriptional modifications, e.g., naturally occurring post-transcriptional modifications; (n) Functional properties of tRNA, for example, the ability to inhibit any of the properties (h) to (k) possessed by tRNA; (o) The ability to regulate cell fate; (p) Ability to regulate ribosome occupation; (q) The ability to regulate protein translation; (r) Ability to regulate mRNA stability; (s) Ability to regulate protein folding and structure; (t) Ability to regulate protein transduction or compartmentalization; (u) the ability to regulate protein stability; or (v) The ability to regulate signaling pathways, such as cellular signaling pathways.

[0083] In one embodiment, TREM comprises a full-length tRNA molecule or a fragment thereof.

[0084] In one embodiment, TREM includes the following characteristics: (a) to (e).

[0085] In one embodiment, TREM includes the following characteristics: (a) and (c).

[0086] In one embodiment, TREM includes the following characteristics: (a), (c), and (h).

[0087] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (b).

[0088] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (e).

[0089] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (b), and (e).

[0090] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (b), (e), and (g).

[0091] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (m).

[0092] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (g).

[0093] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (b).

[0094] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (e).

[0095] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), (g), (b), and (e).

[0096] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), (g), (b), (e), and (q).

[0097] In one embodiment, TREM is (i) an amino acid-binding domain that binds to an amino acid (e.g., AStD as described in (a) of this specification); and (ii) comprising an anticodon that binds to each codon in the mRNA (e.g., ACHD as described in (c) herein).

[0098] In one embodiment, the TREM includes a mobile RNA linker that provides the covalent bonds of (i) and (ii).

[0099] In one embodiment, TREM mediates protein translation.

[0100] In some embodiments, the TREM includes a linker, e.g., an RNA linker, e.g., a mobile RNA linker, that provides a covalent bond between the first and second structures or domains. In some embodiments, the RNA linker includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ribonucleotides. The TREM may include one or more linkers; for example, in embodiments, the TREM comprising (a), (b), (c), (d), and (e) may have a first linker between the first and second domains, and a second linker between the third domain and another domain.

[0101] For a certain purpose, TREM contains the sequence of formula A: [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2].

[0102] In one embodiment, TREM comprises an RNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof, or differs from it by 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 or fewer ribonucleotides. In one embodiment, TREM comprises an RNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to an RNA sequence listed in Table 1, or a fragment or functional fragment thereof. In some embodiments, the TREM includes a TREM domain, for example, a domain described herein, which is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to an RNA encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof, or differs from it by 1, 2, 3, 4, 5, 10, or 15 or fewer ribonucleotides. In some embodiments, the TREM includes a TREM domain, for example, a domain described herein, which includes an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In some embodiments, the TREM includes a TREM domain, for example, a domain described herein, which includes an RNA sequence encoded by a DNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to a DNA sequence listed in Table 1, or a fragment or functional fragment thereof.

[0103] In one embodiment, the TREM is 76 to 90 nucleotides long. In the embodiment, the TREM or its fragment or functional fragment is 10 to 90 nucleotides, 10 to 80 nucleotides, 10 to 70 nucleotides, 10 to 60 nucleotides, 10 to 50 nucleotides, 10 to 40 nucleotides, 10 to 30 nucleotides, 10 to 20 nucleotides, 20 to 90 nucleotides, 20 to 80 nucleotides, 20 to 70 nucleotides, 20 to 60 nucleotides, 20 to 50 nucleotides, 20 to 40 nucleotides, 30 to 90 nucleotides, 30 to 80 nucleotides, 30 to 70 nucleotides, 30 to 60 nucleotides, or 30 to 50 nucleotides.

[0104] In one embodiment, TREM is aminoacylated, for example, by loading amino acids with aminoacyl-tRNA synthetase.

[0105] In one embodiment, the TREM is unloaded with amino acids, for example, an unloaded TREM (uTREM).

[0106] In some embodiments, the TREM contains tRNA that is shorter than the full length. In embodiments, the TREM may correspond to a naturally occurring or non-naturally occurring fragment of tRNA. Exemplary fragments include the TREM half (e.g., derived from a cleavage in the ACHD, e.g., an anticodon sequence, e.g., a 5' half or a 3' half); the 5' fragment (e.g., derived from a cleavage in the DHD or ACHD, e.g., a fragment containing the 5' end); the 3' fragment (e.g., derived from a cleavage in the THD, e.g., a fragment containing the 3' end); or the internal fragment (e.g., derived from a cleavage in one or more of the ACHD, DHD, or THD).

[0107] When the term "TREM core fragment" is used herein, the sequence of formula B:[L1] y -[ASt Domain 1] x -[L2] y -[DH domain] y -[L3] y -[ACH domain] x-[VL domain] y -[TH domain] y -[L4] y -[ASt Domain 2] x This refers to the part where x=1 and y=0 or 1 in the equation.

[0108] As used herein, "TREM fragment" refers to the portion of TREM, where TREM comprises the sequence of formula A: [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2].

[0109] When the term is used herein, "congenital adapter function TREM" refers to a TREM that mediates initiation or extension by AA (congenital AA) that naturally binds to the anticodon of the TREM.

[0110] When the term is used herein, “reduced expression” refers to a reduction compared to a reference, for example, if modification of a control region or addition of a drug results in a reduction in the expression of the product in question, then that reduction is compared to other similar cells without modification or addition.

[0111] When the term is used herein, “external nucleic acid” refers to a nucleic acid sequence that is not present in the nearest sequence in a reference cell, e.g., the cell into which the external nucleic acid is introduced, or that differs from it by at least one nucleotide. In some embodiments, the external nucleic acid includes a nucleic acid encoding TREM.

[0112] "Foreign TREM" is used in this specification, (a) The reference cell, for example, the cell into which the foreign nucleic acid is introduced, has at least one nucleotide or one post-transcriptional modification that is different from the nearest sequence tRNA; (b) Whether it has been introduced into cells other than the transcribed cell; (c) Whether it is present in cells other than those that exist naturally; or (d) Refers to a TREM that has a non-wild-type expression profile, e.g., a level or distribution (e.g., it is expressed at a higher level than the wild type). In some embodiments, the expression profile may be mediated by a change introduced into the nucleic acid that modulates expression or by the addition of a drug that modulates the expression of an RNA molecule. In some embodiments, an exogenous TREM includes one, two, three, or four of characteristics (a) to (d).

[0113] Where used herein, “GMP-grade composition” refers to a composition that conforms to current Good Manufacturing Practices (cGMP) guidelines or other similar requirements. In some embodiments, a GMP-grade composition may be used as a pharmaceutical product.

[0114] As used herein, the terms “increase” and “decrease” refer to adjustments that result in an increase or decrease in the amount of a particular indicator of function, expression, or activity relative to a reference, respectively. For example, after administration of TREM to cells, tissues, or subjects as described herein, the amount of the indicator markers (e.g., protein translation, mRNA stability, protein folding) as described herein may increase or decrease by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%, 2X, 3X, 5X, or 10X compared to the amount of the marker before administration or compared to the effect of a negative control drug. The indicators may be measured at the time after administration when the administration has had the listed effects, for example, at least 12 hours, 24 hours, 1 week, 1 month, 3 months, or 6 months after the start of treatment.

[0115] When the term is used herein, “increased expression” refers to an increase compared to a reference, for example, if modification of a control region or addition of a drug results in increased expression of the product in question, then that increase is compared to other similar cells without modification or addition.

[0116] "Non-homogeneous adapter functional TREM" refers, as used herein, to a TREM that mediates initiation or extension by AAs other than AAs that naturally bind to the TREM's anticodon (non-homogeneous AAs). In some embodiments, a non-homogeneous adapter functional TREM is also called a misloaded TREM (mTREM).

[0117] "Non-natural sequence," as used herein, refers to a sequence in which adenine is replaced by a residue other than an adenine analog, cytosine is replaced by a residue other than a cytosine analog, guanine is replaced by a residue other than a guanine analog, and uracil is replaced by a residue other than a uracil analog. An analog refers to any possible derivative of ribonucleotide A, G, C, or U. In some embodiments, a sequence having a derivative of any one of ribonucleotides A, G, C, or U is a non-natural sequence.

[0118] When the term is used herein, “pharmaceutical TREM composition” refers to a TREM composition suitable for pharmaceutical use. Typically, a pharmaceutical TREM composition contains pharmaceutical excipients. In some embodiments, TREM may be the sole active ingredient in the pharmaceutical TREM composition. In embodiments, the pharmaceutical TREM composition may contain, substantially no, or pharmaceutically acceptable amounts of, host cell proteins, DNA, e.g., host cell DNA, endotoxins, and bacteria.

[0119] "Post-transcriptional processing," as used herein with respect to the target molecule, e.g., TREM, RNA, or tRNA, refers to covalent modification of the target molecule. In some embodiments, the covalent modification occurs after transcription. In some embodiments, the covalent modification occurs concurrently with transcription. In some embodiments, the modification is performed in vivo, for example, in the cells used to produce TREM. In some embodiments, the modification is performed ex vivo, for example, on TREM isolated from or obtained from the cells that produced TREM. In some embodiments, the post-transcriptional modification is selected from the post-transcriptional modifications listed in Table 2.

[0120] "Synthetic TREM," as used herein, refers to TREM synthesized by or from cells other than those possessing endogenous nucleic acids encoding TREM, for example, synthetic TREM is synthesized by cell-free solid-phase synthesis. Synthetic TREM may have the same or different sequence or tertiary structure as natural tRNA.

[0121] When used herein, “recombinant TREM” refers to TREM expressed in cells that have been modified by human intervention, which have modifications that mediate TREM generation (e.g., the cell contains an exogenous sequence encoding TREM), or modifications that mediate TREM transcriptional expression or post-transcriptional modification. Recombinant TREM may have the same or different sequence, set of post-transcriptional modifications, or tertiary structure as a reference tRNA, e.g., a native tRNA.

[0122] When the term "tRNA" is used herein, it refers to transtransition ribonucleic acid that is naturally present in its natural state.

[0123] When the term "TREM composition" is used herein, it refers to a composition comprising multiple TREMs, multiple TREM core fragments, and / or multiple TREM fragments. A TREM composition may comprise one or more species of TREMs, TREM core fragments, or TREM fragments. In some embodiments, the composition comprises only a single species of TREM, TREM core fragment, or TREM fragment. In some embodiments, the TREM composition comprises a first TREM, TREM core fragment, or TREM fragment species; and a second TREM, TREM core fragment, or TREM fragment species. In some embodiments, the TREM composition comprises X TREMs, TREM core fragments, or TREM fragment species (X = 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the TREMs, TREM core fragments, or TREM fragments have at least 70, 75, 80, 85, 90, or 95, or 100%, identity with the sequences encoded by nucleic acids in Table 1. A TREM composition may comprise one or more species of TREMs, TREM core fragments, or TREM fragments. In some embodiments, the TREM composition is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% dry weight TREM (for liquid compositions, dry weight refers to the weight after substantially all liquid has been removed, e.g., after freeze-drying). In some embodiments, the composition is liquid. In some embodiments, the composition is dry, e.g., freeze-dried material. In some embodiments, the composition is frozen composition. In some embodiments, the composition is sterile. In some embodiments, the composition contains at least 0.5 g, 1.0 g, 5.0 g, 10 g, 15 g, 25 g, 50 g, 100 g, 200 g, 400 g, or 500 g of TREM (e.g., measured by dry weight).

[0124] In one embodiment, at least X% of the TREM in the TREM composition has non-natural modifications at selected positions, where X is 80, 90, 95, 96, 97, 98, 99, or 99.5.

[0125] In one embodiment, at least X% of the TREM in the TREM composition has a non-natural modification at a first position and a non-natural modification at a second position, where X is independently 80, 90, 95, 96, 97, 98, 99, or 99.5. In the embodiment, the modifications at the first and second positions are the same. In the embodiment, the modifications at the first and second positions are different. In the embodiment, the nucleotides at the first and second positions are the same, for example, both being adenine. In the embodiment, the nucleotides at the first and second positions are different, for example, one being adenine and the other being thymine.

[0126] In one embodiment, at least X% of the TREM in the TREM composition has a non-natural modification at a first position, and less than Y% has a non-natural modification at a second position, where X is 80, 90, 95, 96, 97, 98, 99, or 99.5, and Y is 20, 20, 5, 2, 1, 0.1, or 0.01. In the embodiment, the nucleotides at the first and second positions are the same, for example, both being adenine. In the embodiment, the nucleotides at the first and second positions are different, for example, one being adenine and the other being thymine.

[0127] TREM, TREM core fragments, and TREM fragments A “tRNA-based effector molecule” or “TREM” refers to an RNA molecule containing one or more of the characteristics described herein. TREMs described herein include a lock nucleic acid (LNA) moiety or a 2',5'-linked nucleotide. TREMs containing an LNA moiety or a 2',5'-linked nucleotide may further include additional non-natural modifications, for example, those provided in Table 5.

[0128] In one embodiment, the TREM includes a TREM containing an array of formula A; a TREM core fragment containing an array of formula B; or a TREM fragment containing a portion of the TREM containing an array of formula A.

[0129] In one embodiment, TREM includes the sequence of formula A: [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2]. In one embodiment, [VL domain] is optional. In one embodiment, [L1] is optional.

[0130] In one embodiment, the TREM core fragment is an array of formula B:[L1] y -[ASt Domain 1] x -[L2] y -[DH domain] y -[L3] y -[ACH domain] x -[VL domain] y -[TH domain] y -[L4] y -[ASt Domain 2] x The equation includes x=1 and y=0 or 1. In one embodiment, y=0. In another embodiment, y=1; In one embodiment, the TREM fragment comprises a portion of TREM, where TREM comprises the sequence of formula A:[L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2], and the TREM fragment comprises one, two, three or all or any combination of the following: a TREM half (e.g., derived from a cleavage in the anticodon sequence, e.g., a 5' half or a 3' half); a 5' fragment (e.g., derived from a cleavage in the DH domain or ACH domain, e.g., a fragment containing a 5' end); a 3' fragment (e.g., derived from a cleavage in the TH domain, e.g., a fragment containing a 3' end); or an internal fragment (e.g., derived from a cleavage in any one of the ACH domain, DH domain or TH domain). Examples of TREM fragments include TREM halves (e.g., derived from a cleavage in ACHD, e.g., a 5' TREM half or a 3' TREM half), 5' fragments (e.g., derived from a cleavage in DHD or ACHD, e.g., a fragment containing the 5' end), 3' fragments (e.g., derived from a cleavage in THD, e.g., a fragment containing the 3' end of a TREM), or internal fragments (e.g., derived from a cleavage in one or more of ACHD, DHD, or THD).

[0131] In some embodiments, the TREM, TREM core fragment, or TREM fragment may be loaded with an amino acid (e.g., a homogeneous amino acid); may be loaded with a non-homogeneous amino acid (e.g., a misloaded TREM (mTREM)); or may not be loaded with an amino acid (e.g., an unloaded TREM (uTREM)). In some embodiments, the TREM, TREM core fragment, or TREM fragment may be loaded with an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0132] In some embodiments, the unextended anticodon is an anticodon of three or fewer nucleotides. In some embodiments, the unextended codon pairs with three or fewer codon nucleotides on the nucleic acid being translated.

[0133] In some embodiments, the TREM, TREM core fragment, or TREM fragment is a cognate TREM. In some embodiments, the TREM, TREM core fragment, or TREM fragment is a non-cognate TREM. In some embodiments, the TREM, TREM core fragment, or TREM fragment recognizes codons provided in Table 2 or Table 3.

[0134] [Table 2-1]

[0135] [Table 2-2]

[0136] [Table 3]

[0137] In one embodiment, the TREM includes a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence disclosed in Table 1, for example, one of the SEQ ID NOs. 1 to 451 disclosed in Table 1. In another embodiment, the TREM includes an RNA sequence that is at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the DNA sequence provided in Table 1, for example, one of the RNA sequences encoded by one of the SEQ ID NOs. 1 to 451 disclosed in Table 1. In one embodiment, the TREM includes an RNA sequence encoded by a DNA sequence that is at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of the DNA sequences provided in Table 1, e.g., SEQ ID NOs 1 to 451 disclosed in Table 1.

[0138] In one embodiment, a TREM, TREM core fragment, or TREM fragment contains at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA sequence disclosed in Table 1, for example, at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by any one of SEQ ID NOs. 1 to 451 disclosed in Table 1. In one embodiment, a TREM, TREM core fragment, or TREM fragment contains at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence that is at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the DNA sequence provided in Table 1, for example, an RNA sequence encoded by any one of SEQ ID NOs. 1 to 451 disclosed in Table 1. In one embodiment, the TREM, TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA sequence that is at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of the SEQ ID NOs. 1 to 451 disclosed in Table 1.

[0139] In one embodiment, the TREM core fragment or TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the DNA sequence provided in Table 1, for example, the RNA sequence encoded by any one of SEQ ID NOs. In one embodiment, the TREM core fragment or TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of an RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the DNA sequence provided in Table 1, for example, the RNA sequence encoded by any one of SEQ ID NOs. In one embodiment, the TREM core fragment or TREM fragment includes at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 98%, or 99% of an RNA sequence encoded by a DNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of the DNA sequences provided in Table 1, e.g., SEQ ID NOs 1 to 451 disclosed in Table 1.

[0140] In one embodiment, the TREM core fragment or TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt, or 60 nt (but less than the full length) of an RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the DNA sequence provided in Table 1, for example, an RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at least 60% identical to the DNA sequence provided in Table 1, for example, an60% identical to the DNA sequence that is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the RNA sequence that is at In one embodiment, the TREM core fragment or TREM fragment includes at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt, or 60 nt (but less than the full length) of an RNA sequence encoded by a DNA sequence having at least 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, 99%, or 100% identity with any one of SEQ ID NOs. 1 to 451 disclosed in Table 1.

[0141] In one embodiment, the TREM core fragment or TREM fragment includes a sequence of lengths of 10-90 ribonucleotides (rnt), 10-80 rnt, 10-70 rnt, 10-60 rnt, 10-50 rnt, 10-40 rnt, 10-30 rnt, 10-20 rnt, 20-90 rnt, 20-80 rnt, 20-70 rnt, 20-60 rnt, 20-50 rnt, 20-40 rnt, 30-90 rnt, 30-80 rnt, 30-70 rnt, 30-60 rnt, or 30-50 rnt.

[0142] [Table 1-1]

[0143] Table 1-2

[0144] Table 1-3

[0145] Table 1-4

[0146] Table 1-5

[0147] Table 1-6

[0148] Table 1-7

[0149] Table 1-8

[0150] Table 1-9

[0151] Table 1-10

[0152] Table 1-11

[0153] Table 1-12

[0154] Table 1-13

[0155] Table 1-14

[0156] Table 1-15

[0157] Table 1-16

[0158] Table 1-17

[0159] Table 1-18

[0160] Table 1-19

[0161] Table 1-20

[0162] Table 1-21

[0163] Table 1-22

[0164] Table 1-23

[0165] Table 1-24

[0166] Table 1-25

[0167] Table 1-26

[0168] Table 1-27

[0169] Table 1-28

[0170] Table 1-29

[0171] Table 1-30

[0172] Table 1-31

[0173] Non-natural decoration The TREMs, TREM core fragments, or TREM fragments described herein include unnatural modifications, such as those listed in Table 5. These unnatural modifications may be prepared according to methods known in the art. An exemplary method for preparing unnatural modifications is provided in Example 1.

[0174] In one embodiment, a non-native modification is a modification that cells, such as human cells, do not produce on endogenous tRNA.

[0175] In some embodiments, the non-native modification is a modification that a cell, such as a human cell, may make on endogenous tRNA, but such a modification is located at a position where it does not occur on native tRNA. In some embodiments, the non-native modification is located in a domain, linker, or arm where such a modification does not occur naturally. In some embodiments, the non-native modification is located at a position within a domain, linker, or arm where such a modification does not occur naturally. In some embodiments, the non-native modification is located on a nucleotide where such a modification does not occur naturally. In some embodiments, the non-native modification is located on a nucleotide at a position within a domain, linker, or arm where such a modification does not occur naturally.

[0176] In some embodiments, the TREM, TREM core fragment, or TREM fragment described herein includes the modifications provided in Table 5, or combinations thereof. The modifications provided in Table 5 are used on synthetic TREM, TREM core fragment, or TREM fragment at positions in RNA that are not naturally present or, as used herein, not naturally present.

[0177] [Table 5-1]

[0178] [Table 5-2]

[0179] [Table 5-3]

[0180] Table 5-4

[0181] Table 5-5

[0182] Table 5-6

[0183] Table 5-7

[0184] Table 5-8

[0185] Table 5-9

[0186] Table 5-10

[0187] Table 5-11

[0188] Table 5-12

[0189] Chemically modified TREM This disclosure features TREMs comprising a lock nucleic acid (LNA) moiety or a 2',5'-linked nucleotide, as described herein. In some embodiments, the TREM may comprise both an LNA moiety and a 2',5'-linked nucleotide, optionally further comprising at least one additional non-natural modification. In some embodiments, the TREM comprising an LNA moiety or a 2',5'-linked nucleotide further comprises at least one additional non-natural modification (e.g., a 2'-ribose modification or an internucleotide modification, e.g., 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothiolate modification).

[0190] Rock Nucleic Acid TREMs comprising nucleotides containing a lock nucleic acid moiety are described herein. The term “lock nucleic acid (LNA) moiety,” as used herein, refers to a nucleotide comprising a modified nucleotide sugar in which the 2'-carbon is bonded to the 4'-carbon atom via a cyclic structure. In some embodiments, the LNA moiety comprises a heterocyclyl ring or cycloalkyl ring between the 2' and 4' positions of the nucleotide sugar within the nucleotide. In some embodiments, the TREM comprises the sequence of formula (I), where the heterocyclyl ring comprises an oxygen atom, a nitrogen atom, a sulfur atom, and a selenium atom. In some embodiments, the heterocyclyl ring or cycloalkyl ring is a 5-membered, 6-membered, 7-membered, or 8-membered ring.

[0191] In one embodiment, this disclosure relates to formula (II): [ka] A TREM characterized by containing a nucleotide having the structure of an LNA moiety, or a salt thereof, stereoisomer, tautomer, or hydrate thereof, wherein B is a nucleic acid base; and Y is C(R'), O, or N(R'). B ) and; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -ORA , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 substituted by arbitrary selection; L and X are independently C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(R E ) y -where each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 substituted by choice; M and Z are absent, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-, S(R D ) x -Se(R E ) y Here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Band R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11 Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 but is hydrogen or a C1-C6 alkyl group; and x and y are independently 0, 1, or 2; [ka] However, this refers to the rest of the TREM sequence, another atom, or a bond point to the end of the TREM; where L, M, Z, and two or fewer Zs are -O-, -N(R B )-, S(R D ) x -Se(R E ) y It is possible that L, M, Z, and one of Z are O-, -N(R B )-, S(R D ) x -Se(R E ) y If so, each direct covalent partner selected from L, M, Z, and X is also O-, -N(R B )-, S(R D ) x -Se(R E ) y No.

[0192] In some embodiments, B is a native nucleic acid base (e.g., adenine, cytosine, guanine, uracil). In some embodiments, B is a purine nucleic acid base. In some embodiments, B is a pyrimidine nucleic acid base. In some embodiments, B is adenine. In some embodiments, B is cytosine. In some embodiments, B is guanine. In some embodiments, B is uracil. In some embodiments, B is a non-native nucleic acid base. In some embodiments, B includes chemical modifications (e.g., natural or non-natural chemical modifications).

[0193] In some embodiments, the chemical modification is a nucleotide sugar modification, a nucleic acid base modification, or an internucleotide bond modification. In some embodiments, the chemical modification is a nucleotide sugar modification. In some embodiments, the chemical modification is a 2'OMe modification. In some embodiments, the chemical modification is a 2'halo (e.g., 2'F or 2'Cl) modification. In some embodiments, the chemical modification is a 2'MOE modification. In some embodiments, the chemical modification is a 2'-deoxy modification. In some embodiments, the chemical modification is located in an internucleotide region (e.g., a skeletal modification). In some embodiments, the chemical modification is a phosphorothioate modification.

[0194] In some embodiments, B does not contain any chemical modifications (e.g., natural or non-natural chemical modifications).

[0195] In some embodiments, Y is selected from CH2, S, or O. In one embodiment, Y is CH2. In another embodiment, Y is S. In yet another embodiment, Y is O.

[0196] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 1is hydrogen. In one embodiment, R 1 is a C1-C6 alkyl group. In one embodiment, R 1 is a C1-C6 heteroalkyl group. In one embodiment, R 1 is a C1-C6 haloalkyl. In one embodiment, R 1 It is a halo.

[0197] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 2 is hydrogen. In one embodiment, R 2 is a C1-C6 alkyl group. In one embodiment, R 2 is a C1-C6 heteroalkyl group. In one embodiment, R 2 is a C1-C6 haloalkyl. In one embodiment, R 2 It is a halo.

[0198] In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 3 is hydrogen. In one embodiment, R 3 is a C1-C6 alkyl group. In one embodiment, R 3 is a C1-C6 heteroalkyl group. In one embodiment, R 3 is a C1-C6 haloalkyl. In one embodiment, R 3 It is a halo.

[0199] In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R 4a and R 4b Each of them is independently hydrogen. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4b Each of these is independently a halo. In one embodiment, R 4a and R 4b One of them is hydrogen, independently. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b One of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4b One of them, independently, is Haro.

[0200] In some embodiments, one of L, M, Z, and X is O. In some embodiments, one of L, M, Z, and X is N(R B )-. In some embodiments, one of L and X is O. In some embodiments, one of L and X is N(R B )-. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S(R D ) x -, and -Se(R E ) y- Selected from. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S, and Se are selected. In some embodiments, X is O. In some embodiments, X is C1-C6 alkylene. In some embodiments, X is N(R B ) In some embodiments, X is S. In some embodiments, X is Se.

[0201] In some embodiments, TREM is expressed by formula (II-a): [ka] It contains a nucleotide comprising an LNA moiety having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, wherein Y is C(R'), O, or N(R B ) and; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 The following are substituted by choice; L and Z are independently C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(R E ) y -where each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 substituted by choice; M and Z are absent, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(RB )-, S(R D ) x -Se(R E ) y Here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11 Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R ia , R ib , R ii , and R iiiEach of them is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo; each of x and y is independently 0, 1, or 2; [ka] However, this refers to the rest of the TREM sequence, another atom, or a bond point to the end of the TREM; where L, M, Z, and two or fewer Zs are -O-, -N(R B )-, S(R D ) x -Se(R E ) y It is possible that L, M, Z, and one of Z are O-, -N(R B )-, S(R D ) x -Se(R E ) y If so, each direct covalent partner selected from L, M, Z, and X is also O-, -N(R B )-, S(R D ) x -Se(R E ) y No.

[0202] In some embodiments, Y is selected from CH2, S, or O. In one embodiment, Y is CH2. In another embodiment, Y is S. In yet another embodiment, Y is O.

[0203] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 1 is hydrogen. In one embodiment, R 1 is a C1-C6 alkyl group. In one embodiment, R 1 is a C1-C6 heteroalkyl group. In one embodiment, R 1 is a C1-C6 haloalkyl. In one embodiment, R 1It is a halo.

[0204] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 2 is hydrogen. In one embodiment, R 2 is a C1-C6 alkyl group. In one embodiment, R 2 is a C1-C6 heteroalkyl group. In one embodiment, R 2 is a C1-C6 haloalkyl. In one embodiment, R 2 It is a halo.

[0205] In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 3 is hydrogen. In one embodiment, R 3 is a C1-C6 alkyl group. In one embodiment, R 3 is a C1-C6 heteroalkyl group. In one embodiment, R 3 is a C1-C6 haloalkyl. In one embodiment, R 3 It is a halo.

[0206] In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R 4a and R 4b Each of them is independently hydrogen. In one embodiment, R 4aand R 4b Each of these is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4b Each of these is independently a halo. In one embodiment, R 4a and R 4b One of them is hydrogen, independently. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b One of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4b One of them, independently, is Haro.

[0207] In some embodiments, one of L, M, Z, and X is O. In some embodiments, one of L, M, Z, and X is N(R B )-. In some embodiments, one of L and X is O. In some embodiments, one of L and X is N(R B )-. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S(R D ) x -, and -Se(R E ) y - Selected from. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S, and Se are selected. In some embodiments, X is O. In some embodiments, X is C1-C6 alkylene. In some embodiments, X is N(R B) In some embodiments, X is S. In some embodiments, X is Se.

[0208] In some embodiments, R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, or a C1-C6 haloalkyl group. In some embodiments, R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R ia and R ib Each of them is independently hydrogen. In one embodiment, R ia and R ib Each of these is independently a C1-C6 alkyl group. In one embodiment, R ia and R ib Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R ia and R ib Each of these is independently a C1-C6 haloalkyl. In one embodiment, R ia and R ib One of them is hydrogen, independently. In one embodiment, R ia and R ib One of them is independently a C1-C6 alkyl group. In one embodiment, R ia and R ib One of them is independently a C1-C6 heteroalkyl. In one embodiment, R ia and R ib One of these is, independently, a C1-C6 haloalkyl group.

[0209] In some embodiments, R ii and R iii Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R ii and R iii Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, Rii and R iii Each of them is independently hydrogen. In one embodiment, R ii and R iii Each of these is independently a C1-C6 alkyl group. In one embodiment, R ii and R iii Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R ii and R iii Each of these is independently a C1-C6 haloalkyl. In one embodiment, R ii and R iii Each of these is independently a halo. In one embodiment, R ii and R iii One of them is hydrogen, independently. In one embodiment, R ii and R iii One of them is independently a C1-C6 alkyl group. In one embodiment, R ii and R iii One of them is independently a C1-C6 heteroalkyl. In one embodiment, R ii and R iii One of these is independently a C1-C6 haloalkyl. In one embodiment, R ii and R iii One of them, independently, is Haro.

[0210] In some embodiments, TREM is given by formula (II-b): [ka] It contains a nucleotide comprising an LNA moiety having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, wherein Y is C(R'), O, or N(R B ) and; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 The following are substituted by choice; L and Z are independently C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(R E ) y -where each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 substituted by choice; M and Z are absent, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-, S(R D ) x -Se(R E ) y Here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R CEach of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11 Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R ia , R ib , R ii , and R iii Each of them is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo; each of x and y is independently 0, 1, or 2; [ka] However, this refers to the rest of the TREM sequence, another atom, or a bond point to the end of the TREM; where L, M, Z, and two or fewer Zs are -O-, -N(R B )-, S(R D ) x -Se(R E ) y It is possible that L, M, Z, and one of Z are O-, -N(R B )-, S(R D ) x -Se(R E ) y If so, each direct covalent partner selected from L, M, Z, and X is also O-, -N(R B )-, S(R D ) x -Se(R E ) y No.

[0211] In some embodiments, Y is selected from CH2, S, or O. In one embodiment, Y is CH2. In another embodiment, Y is S. In yet another embodiment, Y is O.

[0212] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 1 is hydrogen. In one embodiment, R 1 is a C1-C6 alkyl group. In one embodiment, R 1 is a C1-C6 heteroalkyl group. In one embodiment, R 1 is a C1-C6 haloalkyl. In one embodiment, R 1 It is a halo.

[0213] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 2 is hydrogen. In one embodiment, R 2 is a C1-C6 alkyl group. In one embodiment, R 2 is a C1-C6 heteroalkyl group. In one embodiment, R 2 is a C1-C6 haloalkyl. In one embodiment, R 2 It is a halo.

[0214] In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 3 is hydrogen. In one embodiment, R 3is a C1-C6 alkyl group. In one embodiment, R 3 is a C1-C6 heteroalkyl group. In one embodiment, R 3 is a C1-C6 haloalkyl. In one embodiment, R 3 It is a halo.

[0215] In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R 4a and R 4b Each of them is independently hydrogen. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4b Each of these is independently a halo. In one embodiment, R 4a and R 4b One of them is hydrogen, independently. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b One of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4b One of them, independently, is Haro.

[0216] In some embodiments, one of L, M, Z, and X is O. In some embodiments, one of L, M, Z, and X is N(R B )-. In some embodiments, one of L and X is O. In some embodiments, one of L and X is N(R B )-. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S(R D ) x -, and -Se(R E ) y - Selected from. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S, and Se are selected. In some embodiments, X is O. In some embodiments, X is C1-C6 alkylene. In some embodiments, X is N(R B ) In some embodiments, X is S. In some embodiments, X is Se.

[0217] In some embodiments, R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, or a C1-C6 haloalkyl group. In some embodiments, R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R ia and R ib Each of them is independently hydrogen. In one embodiment, R ia and R ib Each of these is independently a C1-C6 alkyl group. In one embodiment, R ia and R ib Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R ia and R ib Each of these is independently a C1-C6 haloalkyl. In one embodiment, R ia and R ib One of them is hydrogen, independently. In one embodiment, R iaand R ib One of them is independently a C1-C6 alkyl group. In one embodiment, R ia and R ib One of them is independently a C1-C6 heteroalkyl. In one embodiment, R ia and R ib One of these is, independently, a C1-C6 haloalkyl group.

[0218] In some embodiments, R ii and R iii Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R ii and R iii Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R ii and R iii Each of them is independently hydrogen. In one embodiment, R ii and R iii Each of these is independently a C1-C6 alkyl group. In one embodiment, R ii and R iii Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R ii and R iii Each of these is independently a C1-C6 haloalkyl. In one embodiment, R ii and R iii Each of these is independently a halo. In one embodiment, R ii and R iii One of them is hydrogen, independently. In one embodiment, R ii and R iii One of them is independently a C1-C6 alkyl group. In one embodiment, R ii and R iii One of them is independently a C1-C6 heteroalkyl. In one embodiment, R ii and R iii One of these is independently a C1-C6 haloalkyl. In one embodiment, R ii and R iiiOne of them, independently, is Haro.

[0219] In some embodiments, TREM is expressed by formula (II-c): [ka] It contains a nucleotide comprising an LNA moiety having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, wherein Y is C(R'), O, or N(R B ) and; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 The following are substituted by choice; L and Z are independently C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(R E ) y -where each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 substituted by choice; M and Z are absent, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-, S(R D ) x -Se(R E ) y Here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; R 4a and R4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11 Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R ia , R ib , R ii , and R iii Each of them is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo; each of x and y is independently 0, 1, or 2; [ka] However, this refers to the rest of the TREM sequence, another atom, or a bond point to the end of the TREM; where L, M, Z, and two or fewer Zs are -O-, -N(RB )-, S(R D ) x -Se(R E ) y It is possible that L, M, Z, and one of Z are O-, -N(R B )-, S(R D ) x -Se(R E ) y If so, each direct covalent partner selected from L, M, Z, and X is also O-, -N(R B )-, S(R D ) x -Se(R E ) y No.

[0220] In some embodiments, Y is selected from CH2, S, or O. In one embodiment, Y is CH2. In another embodiment, Y is S. In yet another embodiment, Y is O.

[0221] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 1 is hydrogen. In one embodiment, R 1 is a C1-C6 alkyl group. In one embodiment, R 1 is a C1-C6 heteroalkyl group. In one embodiment, R 1 is a C1-C6 haloalkyl. In one embodiment, R 1 It is a halo.

[0222] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 2 is hydrogen. In one embodiment, R2 is a C1-C6 alkyl group. In one embodiment, R 2 is a C1-C6 heteroalkyl group. In one embodiment, R 2 is a C1-C6 haloalkyl. In one embodiment, R 2 It is a halo.

[0223] In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 3 is hydrogen. In one embodiment, R 3 is a C1-C6 alkyl group. In one embodiment, R 3 is a C1-C6 heteroalkyl group. In one embodiment, R 3 is a C1-C6 haloalkyl. In one embodiment, R 3 It is a halo.

[0224] In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R 4a and R 4b Each of them is independently hydrogen. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4bEach of these is independently a halo. In one embodiment, R 4a and R 4b One of them is hydrogen, independently. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b One of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4b One of them, independently, is Haro.

[0225] In some embodiments, one of L, M, Z, and X is O. In some embodiments, one of L, M, Z, and X is N(R B )-. In some embodiments, one of L and X is O. In some embodiments, one of L and X is N(R B )-. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S(R D ) x -, and -Se(R E ) y - Selected from. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S, and Se are selected. In some embodiments, X is O. In some embodiments, X is C1-C6 alkylene. In some embodiments, X is N(R B ) In some embodiments, X is S. In some embodiments, X is Se.

[0226] In some embodiments, R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, or a C1-C6 haloalkyl group. In some embodiments, R ia and R ibEach of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R ia and R ib Each of them is independently hydrogen. In one embodiment, R ia and R ib Each of these is independently a C1-C6 alkyl group. In one embodiment, R ia and R ib Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R ia and R ib Each of these is independently a C1-C6 haloalkyl. In one embodiment, R ia and R ib One of them is hydrogen, independently. In one embodiment, R ia and R ib One of them is independently a C1-C6 alkyl group. In one embodiment, R ia and R ib One of them is independently a C1-C6 heteroalkyl. In one embodiment, R ia and R ib One of these is, independently, a C1-C6 haloalkyl group.

[0227] In some embodiments, R ii and R iii Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R ii and R iii Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R ii and R iii Each of them is independently hydrogen. In one embodiment, R ii and R iii Each of these is independently a C1-C6 alkyl group. In one embodiment, R ii and R iii Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R ii and R iiiEach of these is independently a C1-C6 haloalkyl. In one embodiment, R ii and R iii Each of these is independently a halo. In one embodiment, R ii and R iii One of them is hydrogen, independently. In one embodiment, R ii and R iii One of them is independently a C1-C6 alkyl group. In one embodiment, R ii and R iii One of them is independently a C1-C6 heteroalkyl. In one embodiment, R ii and R iii One of these is independently a C1-C6 haloalkyl. In one embodiment, R ii and R iii One of them, independently, is Haro.

[0228] In some embodiments, TREM is given by equation (II-d): [ka] It contains a nucleotide comprising an LNA moiety having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, wherein Y is C(R'), O, or N(R B ) and; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 The following are substituted by choice; L and Z are independently C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(RE ) y -where each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 substituted by choice; M and Z are absent, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-, S(R D ) x -Se(R E ) y Here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R i , R ii , and R iii Each of them is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo; each of x and y is independently 0, 1, or 2; [ka] However, this refers to the rest of the TREM sequence, another atom, or a bond point to the end of the TREM; where L, M, Z, and two or fewer Zs are -O-, -N(R B )-, S(R D ) x -Se(R E ) y It is possible that L, M, Z, and one of Z are O-, -N(R B )-, S(R D ) x -Se(R E ) y If so, each direct covalent partner selected from L, M, Z, and X is also O-, -N(R B )-, S(R D ) x -Se(R E ) y No.

[0229] In some embodiments, Y is selected from CH2, S, or O. In one embodiment, Y is CH2. In another embodiment, Y is S. In yet another embodiment, Y is O.

[0230] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 1 is hydrogen. In one embodiment, R1 is a C1-C6 alkyl group. In one embodiment, R 1 is a C1-C6 heteroalkyl group. In one embodiment, R 1 is a C1-C6 haloalkyl. In one embodiment, R 1 It is a halo.

[0231] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 2 is hydrogen. In one embodiment, R 2 is a C1-C6 alkyl group. In one embodiment, R 2 is a C1-C6 heteroalkyl group. In one embodiment, R 2 is a C1-C6 haloalkyl. In one embodiment, R 2 It is a halo.

[0232] In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 3 is hydrogen. In one embodiment, R 3 is a C1-C6 alkyl group. In one embodiment, R 3 is a C1-C6 heteroalkyl group. In one embodiment, R 3 is a C1-C6 haloalkyl. In one embodiment, R 3 It is a halo.

[0233] In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 4a and R4b Each of them is independently hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In certain embodiments, R 4a and R 4b are each independently hydrogen. In certain embodiments, R 4a and R 4b are each independently C1-C6 alkyl. In certain embodiments, R 4a and R 4b are each independently C1-C6 heteroalkyl. In certain embodiments, R 4a and R 4b are each independently C1-C6 haloalkyl. In certain embodiments, R 4a and R 4b are each independently halo. In certain embodiments, one of R 4a and R 4b is independently hydrogen. In certain embodiments, one of R 4a and R 4b is independently C1-C6 alkyl. In certain embodiments, one of R 4a and R 4b is independently C1-C6 heteroalkyl. In certain embodiments, one of R 4a and R 4b is independently C1-C6 haloalkyl. In certain embodiments, one of R 4a and R 4b is independently halo.

[0234] In some embodiments, one of L, M, Z, and X is O. In some embodiments, one of L, M, Z, and X is N(R B ). In some embodiments, one of L and X is O. In some embodiments, one of L and X is N(R B ). In some embodiments, X is C1-C6 alkylene, O, N(R B ), S(R D ) x -, and -Se(R E ) y- selected from. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S, and Se. In some embodiments, X is O. In some embodiments, X is C1-C6 alkylene. In some embodiments, X is N(R B ). In some embodiments, X is S. In some embodiments, X is Se.

[0235] In some embodiments, R i is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl. In some embodiments, R i is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl. In certain embodiments, R i is hydrogen. In certain embodiments, R i is C1-C6 alkyl. In certain embodiments, R i is C1-C6 heteroalkyl. In certain embodiments, R i is C1-C6 haloalkyl.

[0236] In some embodiments, each of R ii and R iii is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, each of R ii and R iii is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl. In certain embodiments, each of R ii and R iii is independently hydrogen. In certain embodiments, each of R ii and R iii is independently C1-C6 alkyl. In certain embodiments, each of R ii and R iii is independently C1-C6 heteroalkyl. In certain embodiments, each of R ii and R iii is independently C1-C6 haloalkyl. In certain embodiments, each of R iiand R iii Each of these is independently a halo. In one embodiment, R ii and R iii One of them is hydrogen, independently. In one embodiment, R ii and R iii One of them is independently a C1-C6 alkyl group. In one embodiment, R ii and R iii One of them is independently a C1-C6 heteroalkyl. In one embodiment, R ii and R iii One of these is independently a C1-C6 haloalkyl. In one embodiment, R ii and R iii One of them, independently, is Haro.

[0237] In some embodiments, TREM is given by formula (II-e): [ka] A nucleotide containing an LNA moiety having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, wherein B is a nucleic acid base; and Y is C(R'), O, or N(R'). B ) and; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 The following are substituted by choice; X is C1~C6 alkylene, C2~C6 alkenylene, C2~C6 alkynylene, C1~C6 heteroalkylene, C1~C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(R E ) y- and wherein each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is optionally substituted with one or more R 11 ; R 4a and R 4b each independently is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R 10 ; R 5a and R 5b each independently is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R 10 ; R' is hydrogen or C1-C6 alkyl; each R A is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C each independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C together with the atom to which they are attached form a 3- to 7-membered heterocyclyl ring optionally substituted with one or more R 11 ; each R D and R E are independently C1-C6 alkyl or oxo; R 10 and R 11Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 is hydrogen or a C1-C6 alkyl group; x and y are independently 0, 1, or 2; and n is 1, 2, 3, 4, 5, or 6; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0238] In some embodiments, Y is selected from CH2, S, or O. In one embodiment, Y is CH2. In another embodiment, Y is S. In yet another embodiment, Y is O.

[0239] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 1 is hydrogen. In one embodiment, R 1 is a C1-C6 alkyl group. In one embodiment, R 1 is a C1-C6 heteroalkyl group. In one embodiment, R 1 is a C1-C6 haloalkyl. In one embodiment, R 1 It is a halo.

[0240] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 2 is hydrogen. In one embodiment, R 2 is a C1-C6 alkyl group. In one embodiment, R 2is a C1-C6 heteroalkyl group. In one embodiment, R 2 is a C1-C6 haloalkyl. In one embodiment, R 2 It is a halo.

[0241] In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 3 R is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In one embodiment, R 3 is hydrogen. In one embodiment, R 3 is a C1-C6 alkyl group. In one embodiment, R 3 is a C1-C6 heteroalkyl group. In one embodiment, R 3 is a C1-C6 haloalkyl. In one embodiment, R 3 It is a halo.

[0242] In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 4a and R 4b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R 4a and R 4b Each of them is independently hydrogen. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b Each of these is independently a C1-C6 haloalkyl. In one embodiment, R 4a and R 4b Each of these is independently a halo. In one embodiment, R 4a and R4b One of them is hydrogen, independently. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 alkyl group. In one embodiment, R 4a and R 4b One of them is independently a C1-C6 heteroalkyl. In one embodiment, R 4a and R 4b One of these is independently a C1-C6 haloalkyl. In one embodiment, R 5a and R 5b One of them, independently, is Haro.

[0243] In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R 5a and R 5b Each of them is independently hydrogen. In one embodiment, R 5a and R 5b Each of these is independently a C1-C6 alkyl group. In one embodiment, R 5a and R 5b Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R 5a and R 5b Each of these is independently a C1-C6 haloalkyl. In one embodiment, R 5a and R 5b Each of these is independently a halo. In one embodiment, R 5a and R 5b One of them is hydrogen, independently. In one embodiment, R 5a and R 5b One of them is independently a C1-C6 alkyl group. In one embodiment, R 5a and R 5b One of them is independently a C1-C6 heteroalkyl. In one embodiment, R5a and R 5b One of these is independently a C1-C6 haloalkyl. In one embodiment, R 5a and R 5b One of them, independently, is Haro.

[0244] In some embodiments, X is C1-C6 alkylene, O, N(R) B ), S(R D ) x -, and -Se(R E ) y - Selected from. In some embodiments, X is C1-C6 alkylene, O, N(R B ), S, and Se are selected. In some embodiments, X is O. In some embodiments, X is C1-C6 alkylene. In some embodiments, X is N(R B ) In some embodiments, X is S. In some embodiments, X is Se.

[0245] In some embodiments, n is selected from 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.

[0246] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety are of formula (II-ei) or (II-e-ii): [ka] It has the structure of a salt, stereoisomer, tautomer, or hydrate thereof.

[0247] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety are given by formula (II-f): [ka] , or having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, where B is a nucleic acid base; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 The following are substituted by choice; X is C1~C6 alkylene, C2~C6 alkenylene, C2~C6 alkynylene, C1~C6 heteroalkylene, C1~C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(R E ) y -where each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11 Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 is hydrogen or a C1-C6 alkyl group; x and y are independently 0, 1, or 2; and n is 1, 2, 3, 4, 5, or 6; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0248] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety are of formula (II-fi) or (II-f-ii): [ka] It has the structure of a salt, stereoisomer, tautomer, or hydrate thereof.

[0249] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety having the structure of formula (II-f) are [ka] or selected from its salts, stereoisomers, tautomers, or hydrates.

[0250] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety are given by formula (II-g): [ka] Having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, in the formula: B is a nucleic acid base; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 However, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 is hydrogen or a C1-C6 alkyl group; x and y are independently 0, 1, or 2; and n is 1, 2, 3, 4, 5, or 6; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0251] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety are of formula (II-gi) or formula (II-g-ii): [ka] It has the structure of a salt, stereoisomer, tautomer, or hydrate thereof.

[0252] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety are given by formula (II-g-iii): [ka] It has the structure of a salt, stereoisomer, tautomer, or hydrate thereof.

[0253] In some embodiments, TREM is given by formula (II-l): [ka] A nucleotide containing an LNA moiety having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, wherein B is a nucleic acid base; and Y is C(R'), O, or N(R'). B ) and; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 The following are substituted by choice; X is C1~C6 alkylene, C2~C6 alkenylene, C2~C6 alkynylene, C1~C6 heteroalkylene, C1~C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(R E ) y -where each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; M is absent, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C1-C6 heteroalkylene, C1-C6 haloalkylene -O-, -N(R B )-, S(R D ) x -Se(RE ) y Here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 but is hydrogen or a C1-C6 alkyl group; and x and y are independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0254] In some embodiments, TREM is given by formula (II-m): [ka] A nucleotide containing an LNA moiety having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, wherein B is a nucleic acid base; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5bEach of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 6a and R 6b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11 Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 but is hydrogen or a C1-C6 alkyl group; and x and y are independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0255] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety having the structure of formula (II-l) are [ka] or selected from its salts, stereoisomers, tautomers, or hydrates.

[0256] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety are given by formula (II-mi): [ka] It has the structure of a salt, stereoisomer, tautomer, or hydrate thereof.

[0257] In some embodiments, TREM is given by equation (II-r): [ka] A nucleotide containing an LNA moiety having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, wherein B is a nucleic acid base; and Y is C(R'), O, or N(R'). B ) and; R 1 , R 2 , and R 3 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10The following are substituted by choice; X is C1~C6 alkylene, C2~C6 alkenylene, C2~C6 alkynylene, C1~C6 heteroalkylene, C1~C6 haloalkylene -O-, -N(R B )-,-S(R D ) x -, -Se(R E ) y -where each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R 11 Replaced by optional selection; R 4a and R 4b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 6a and R 6b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 7a and R 7bEach of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E However, they are independently C1-C6 alkyl or oxo; R 10 and R 11 Each of these can independently be a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 but is hydrogen or a C1-C6 alkyl group; and x and y are independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0258] In some embodiments, R 5a and R 5bEach of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R 5a and R 5b Each of them is independently hydrogen. In one embodiment, R 5a and R 5b Each of these is independently a C1-C6 alkyl group. In one embodiment, R 5a and R 5b Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R 5a and R 5b Each of these is independently a C1-C6 haloalkyl. In one embodiment, R 5a and R 5b Each of these is independently a halo. In one embodiment, R 5a and R 5b One of them is hydrogen, independently. In one embodiment, R 5a and R 5b One of them is independently a C1-C6 alkyl group. In one embodiment, R 5a and R 5b One of them is independently a C1-C6 heteroalkyl. In one embodiment, R 5a and R 5b One of these is independently a C1-C6 haloalkyl. In one embodiment, R 5a and R 5b One of them, independently, is Haro.

[0259] In some embodiments, R 6a and R 6b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 6a and R 6b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In one embodiment, R 6a and R6b Each of them is independently hydrogen. In one embodiment, R 6a and R 6b Each of these is independently a C1-C6 alkyl group. In one embodiment, R 6a and R 6b Each of these is independently a C1-C6 heteroalkyl. In one embodiment, R 6a and R 6b Each of these is independently a C1-C6 haloalkyl. In one embodiment, R 6a and R 6b Each of these is independently a halo. In one embodiment, R 6a and R 6b One of them is hydrogen, independently. In one embodiment, R 6a and R 6b One of them is C1-C6 alkyl. In one embodiment, R 6a and R 6b One of them is a C1-C6 heteroalkyl group. In one embodiment, R 6a and R 6b One of these is a C1-C6 haloalkyl group. In one embodiment, R 6a and R 6b One example is halo.

[0260] In some embodiments, the nucleotides in the TREM sequence containing the LNA moiety are of formula (II-s) or formula (II-t): [ka] It has the structure of a salt, stereoisomer, tautomer, or hydrate thereof.

[0261] In some embodiments, the TREM includes one LNA portion. In some embodiments, the TREM includes multiple LNA portions. In some embodiments, the TREM includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 LNA portions. In some embodiments, the TREM includes two LNA portions. In some embodiments, the TREM includes three LNA portions. In some embodiments, the TREM includes four LNA portions. In some embodiments, the TREM includes five LNA portions. In some embodiments, the TREM includes six LNA portions. In some embodiments, the TREM includes at least seven LNA portions.

[0262] In some embodiments, the LNA portion is located in [L1]-[ASt domain 1]-[L2]. In some embodiments, the LNA portion is located in [L1]-[ASt domain 1]-[L2]. In some embodiments, the LNA portion is located in [L2]-[DH domain]-[L3]. In some embodiments, the LNA portion is located in [L3]-[ACH domain]. In some embodiments, the LNA portion is located in the [VL domain]. In some embodiments, the LNA portion is located in the [TH domain]. In some embodiments, the LNA portion is located in [L4]-[ASt domain 2]-[L5].

[0263] In some embodiments, TREM contains lock nucleic acid in the [ASt domain 1]. In some embodiments, TREM contains lock nucleic acid in the [DH domain]. In some embodiments, TREM contains lock nucleic acid in the [ACH domain]. In some embodiments, TREM contains lock nucleic acid in the [VL domain]. In some embodiments, TREM contains lock nucleic acid in the [TH domain]. In some embodiments, TREM contains lock nucleic acid in the [ASt domain 2].

[0264] In one embodiment, the LNA portion is located at one of the nucleotide positions 1, 14, 15, 16, 28, 29, 43, 44, 45, 54, 65, 68, and 70 of the TREM. In another embodiment, the lock nucleic acid is located at one of the nucleotide positions 14, 15, 44, or 54 of the TREM.

[0265] In one embodiment, the lock nucleic acid is absent at one of nucleotide positions 41, 42, or 63 of the TREM. In another embodiment, the lock nucleic acid is absent at nucleotide position 26 of the TREM.

[0266] In some embodiments, TREM comprises two or more lock nucleic acids. In some embodiments, TREM comprises two lock nucleic acids. In some embodiments, TREM comprises two lock nucleic acids independently located in [ASt domain 1] and [VL domain], respectively. In some embodiments, TREM comprises two lock nucleic acids independently located in [ASt domain 1] and [TH domain], respectively. In some embodiments, TREM comprises two lock nucleic acids independently located in [ASt domain 1] and [ASt domain 2], respectively. In some embodiments, TREM comprises two lock nucleic acids independently located at one of nucleotide positions 14, 15, 44, 54, and 65 (e.g., 14 and 15, e.g., 15 and 65, e.g., 14 and 65, or e.g., 14 and 54).

[0267] In some embodiments, TREM includes three lock nucleic acids. In some embodiments, TREM includes three lock nucleic acids independently located in the [ACH domain], [TH domain], and [ASt domain 2]. In some embodiments, TREM includes one lock nucleic acid located in the [ACH domain] and two lock nucleic acids in the [VL domain]. In some embodiments, TREM includes one lock nucleic acid in the [TH domain] and two lock nucleic acids in the [DH domain]. In some embodiments, TREM includes three lock nucleic acids independently located at nucleotide positions 14, 15, 54, or 65 (e.g., 14, 15, and 54; e.g., 14, 15, and 65). In some embodiments, TREM includes three lock nucleic acids independently located at nucleotide positions 14, 15, and 54. In some embodiments, TREM includes three lock nucleic acids independently located at nucleotide positions 14, 15, and 65.

[0268] In some embodiments, TREM comprises four lock nucleic acids located in the [DH domain], [VL domain], [TH domain], and [ASt domain 2]. In some embodiments, TREM comprises four lock nucleic acids located in the [DH domain], [ACH domain], [TH domain], and [ASt domain 2]. In some embodiments, TREM comprises four lock nucleic acids independently located at nucleotide positions 14, 44, 54, and 65, respectively. In some embodiments, TREM comprises four lock nucleic acids independently located at nucleotide positions 14, 43, 54, and 65, respectively.

[0269] In some embodiments, TREM comprises five lock nucleic acids. In some embodiments, TREM comprises six lock nucleic acids. In some embodiments, TREM comprises seven or more lock nucleic acids.

[0270] In some embodiments, the TREM is a TREM having an array of any one of the TREMs provided in Figure 1, for example, sequence numbers 625-793, 992-1252, 1357, 1364, 1378-1393, or 1397-1398 (for example, any one of sequence numbers 625-793, for example, any one of sequence numbers 992-1252, 1357, 1364, 1378-1393, or 1397-1398). In some embodiments, the TREM is a TREM having one of the sequences of sequence numbers 626-793, 992-1252, 1357, 1364, 1378-1393, and 1397-1398, as provided in Figure 1 (for example, a TREM having one of the sequences of sequence numbers 626-793, or a TREM having one of the sequences of sequence numbers 992-1252, 1357, 1364, 1378-1393, and 1397-1398). In some embodiments, the TREM is a TREM having at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more sequence identity with the TREM provided in Figure 1, for example, a TREM having one of the sequences of sequence numbers 626-793. In some embodiments, the TREM is a TREM having at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleotides, which is different from the TREM provided in Figure 1, for example, the TREM having any one sequence of SEQ ID NOs.626-793. In some embodiments, the TREM is a TREM having 1-5, 5-10, 10-15, or 15-20 nucleotides, which is different from the TREM provided in Figure 1, for example, the TREM having any one sequence of SEQ ID NOs.626-793. In some embodiments, the TREM is a TREM having at least one additional non-natural modification compared to the TREM provided in Figure 1, for example, the TREM having any one sequence of SEQ ID NOs.626-793.In some embodiments, the TREM is a TREM having at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more additional non-natural modifications compared to the TREM provided in Figure 1, for example, a TREM having one of the sequences of sequence numbers 626-793.

[0271] In one embodiment, the lock nucleic acid is located at nucleotide positions 14, 15, 44, 54, or 65 of the TREM. In one embodiment, the lock nucleic acid is located at nucleotide position 14 of the TREM. In one embodiment, the lock nucleic acid is located at nucleotide position 15 of the TREM. In one embodiment, the lock nucleic acid is located at nucleotide position 54 of the TREM. In one embodiment, the lock nucleic acid is located at nucleotide position 65 of the TREM.

[0272] In one embodiment, the lock nucleic acid is not located at nucleotide positions 41, 42, or 63 of the TREM.

[0273] In one embodiment, the lock nucleic acid is not located at nucleotide positions 7, 8, 9, 10, 17, 18, 31, 32, 33, 34, 35, 36, 37, 38, 39, 48, 55, 58, 59, 60, 61, 72, or 73 (for example, 7-10, 17-18, 31-39, 48, 55, 58-61, or 72-73).

[0274] In some embodiments, the lock nucleic acid is not located at nucleotide positions 7-10 (e.g., 7, 8, 9, or 10). In some embodiments, the lock nucleic acid is not located at nucleotide position 7. In some embodiments, the lock nucleic acid is not located at nucleotide position 8. In some embodiments, the lock nucleic acid is not located at nucleotide position 9. In some embodiments, the lock nucleic acid is not located at nucleotide position 10.

[0275] In some embodiments, the lock nucleic acid is not located at nucleotide positions 17-18 (e.g., 17 or 18). In some embodiments, the lock nucleic acid is not located at nucleotide position 17. In some embodiments, the lock nucleic acid is not located at nucleotide position 18. In some embodiments, the lock nucleic acid is not located at nucleotide positions 31-39 (e.g., 31, 32, 33, 34, 35, 36, 37, 38, or 39). In some embodiments, the lock nucleic acid is not located at nucleotide position 31. In some embodiments, the lock nucleic acid is not located at nucleotide position 32. In some embodiments, the lock nucleic acid is not located at nucleotide position 33. In some embodiments, the lock nucleic acid is not located at nucleotide position 34. In some embodiments, the lock nucleic acid is not located at nucleotide position 35. In some embodiments, the lock nucleic acid is not located at nucleotide position 36. In some embodiments, the lock nucleic acid is not located at nucleotide position 37. In some embodiments, the lock nucleic acid is not located at nucleotide position 38. In some embodiments, the lock nucleic acid is not located at nucleotide position 39.

[0276] In one embodiment, the lock nucleic acid is not located at nucleotide position 48.

[0277] In one embodiment, the lock nucleic acid is not located at nucleotide position 55.

[0278] In some embodiments, the lock nucleic acid is not located at nucleotide positions 58-61 (e.g., 58, 59, 60, or 61). In some embodiments, the lock nucleic acid is not located at nucleotide position 58. In some embodiments, the lock nucleic acid is not located at nucleotide position 59. In some embodiments, the lock nucleic acid is not located at nucleotide position 60. In some embodiments, the lock nucleic acid is not located at nucleotide position 61.

[0279] In some embodiments, the lock nucleic acid is not located at nucleotide positions 72-73 (e.g., 72 or 73). In some embodiments, the lock nucleic acid is not located at nucleotide position 72. In some embodiments, the lock nucleic acid is not located at nucleotide position 73.

[0280] In some embodiments, TREM is a non-natural modification pattern of TREM number 166 in Figure 1: 1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-f, 14-LNA, 16-m, 17-m, 19-*, 22-m, 25-m, 27-m*, 28-f, 29-moe, 33-f, 35-*, 37-*, 38- *, 41-m, 42-m, 43-LNA, 44-f, 45-LNA, 46-d, 49-m, 50-m, 51-m, 52-d, 53-m, 54-LNA, 55-*, 56-m , 57-f, 60-f, 61-m, 62-m, 63-f*, 64-d, 65-LNA, 66-m, 67-m, 68-f, 71-m, 72-f, 73-m, 75-f*.

[0281] In some embodiments, TREM is a non-natural modification pattern of TREM number 167 in Figure 1: 1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-f, 14-LNA, 15-f, 16-m, 17-m, 19-*, 21-f, 22-m, 25-m, 27-m*, 28-f, 29-moe, 33-f, 35-*, 37-*, 38- *, 40-f, 41-m, 42-m, 43-LNA, 44-f, 45-LNA, 46-d, 49-m, 50-m, 51-m, 52-d, 53-m, 54-LNA, 55-*, 56-m , 57-f, 59-f, 60-f, 61-m, 62-m, 63-f*, 64-d, 65-LNA, 66-m, 67-m, 68-f, 71-m, 72-f, 73-m, 75-f*.

[0282] In some embodiments, TREM is a non-natural modification pattern of TREM number 168 in Figure 1: 1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 13-f, 15-f, 17-m, 19-*, 20-d, 21-f, 22-m, 25-m, 27-m*, 28-f, 29-moe, 33-f, 35-*, 37-*, 38-*, 40 -f, 41-m, 42-m, 43-LNA, 44-f, 45-LNA, 46-d, 49-m, 50-m, 51-m, 52-d, 53-m, 54-LNA, 55-*, 56-m , 57-f, 59-f, 60-f, 61-m, 62-m, 63-f*, 64-d, 65-LNA, 66-m, 67-m, 68-f, 72-f, 73-m, 75-f*.

[0283] In some embodiments, the TREM is a non-natural modification pattern of TREM number 169 in Figure 1: 1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 13-f, 17-m, 19-*, 22-m, 25-m, 27-m*, 28-f, 29-moe, 33-f, 35-*, 37-*, 38-*, 41-m , 42-m, 43-LNA, 44-f, 45-LNA, 46-d, 49-m, 50-m, 51-m, 52-d, 53-m, 54-LNA, 55-*, 56-m, Includes 57-f, 60-f, 61-m, 62-m, 63-f*, 64-d, 65-LNA, 66-m, 67-m, 68-f, 72-f, 73-m, 75-f*.

[0284] In some embodiments, the TREM containing the LNA portion is TREM number 15. In some embodiments, the TREM containing the LNA portion is TREM number 16. In some embodiments, the TREM containing the LNA portion is TREM number 43. In some embodiments, the TREM containing the LNA portion is TREM number 44. In some embodiments, the TREM containing the LNA portion is TREM number 45. In some embodiments, the TREM containing the LNA portion is TREM number 46. In some embodiments, the TREM containing the LNA portion is TREM number 66. In some embodiments, the TREM containing the LNA portion is TREM number 79. In some embodiments, the TREM containing the LNA portion is TREM number 80. In some embodiments, the TREM containing the LNA portion is TREM number 81. In some embodiments, the TREM containing the LNA portion is TREM number 82. In some embodiments, the TREM containing the LNA portion is TREM number 83. In some embodiments, the TREM containing the LNA portion is TREM number 84. In some embodiments, the TREM containing the LNA portion is TREM number 85. In some embodiments, the TREM containing the LNA portion is TREM number 86. In some embodiments, the TREM containing the LNA portion is TREM number 87. In some embodiments, the TREM containing the LNA portion is TREM number 88. In some embodiments, the TREM containing the LNA portion is TREM number 89. In some embodiments, the TREM containing the LNA portion is TREM number 90. In some embodiments, the TREM containing the LNA portion is TREM number 91. In some embodiments, the TREM containing the LNA portion is TREM number 92. In some embodiments, the TREM containing the LNA portion is TREM number 93. In some embodiments, the TREM containing the LNA portion is TREM number 94. In some embodiments, the TREM containing the LNA portion is TREM number 95. In some embodiments, the TREM containing the LNA portion is TREM number 96.In some embodiments, the TREM containing the LNA portion is TREM number 97. In some embodiments, the TREM containing the LNA portion is TREM number 98. In some embodiments, the TREM containing the LNA portion is TREM number 99. In some embodiments, the TREM containing the LNA portion is TREM number 100. In some embodiments, the TREM containing the LNA portion is TREM number 101. In some embodiments, the TREM containing the LNA portion is TREM number 102. In some embodiments, the TREM containing the LNA portion is TREM number 103. In some embodiments, the TREM containing the LNA portion is TREM number 104. In some embodiments, the TREM containing the LNA portion is TREM number 105. In some embodiments, the TREM containing the LNA portion is TREM number 106. In some embodiments, the TREM containing the LNA portion is TREM number 107. In some embodiments, the TREM containing the LNA portion is TREM number 108. In some embodiments, the TREM containing the LNA portion is TREM number 109. In some embodiments, the TREM containing the LNA portion is TREM number 110. In some embodiments, the TREM containing the LNA portion is TREM number 111. In some embodiments, the TREM containing the LNA portion is TREM number 112. In some embodiments, the TREM containing the LNA portion is TREM number 113. In some embodiments, the TREM containing the LNA portion is TREM number 114. In some embodiments, the TREM containing the LNA portion is TREM number 115. In some embodiments, the TREM containing the LNA portion is TREM number 116. In some embodiments, the TREM containing the LNA portion is TREM number 117. In some embodiments, the TREM containing the LNA portion is TREM number 118. In some embodiments, the TREM containing the LNA portion is TREM number 120. In some embodiments, the TREM containing the LNA portion is TREM number 121.In some embodiments, the TREM containing the LNA portion is TREM number 122. In some embodiments, the TREM containing the LNA portion is TREM number 123. In some embodiments, the TREM containing the LNA portion is TREM number 124. In some embodiments, the TREM containing the LNA portion is TREM number 125. In some embodiments, the TREM containing the LNA portion is TREM number 126. In some embodiments, the TREM containing the LNA portion is TREM number 127. In some embodiments, the TREM containing the LNA portion is TREM number 128. In some embodiments, the TREM containing the LNA portion is TREM number 129. In some embodiments, the TREM containing the LNA portion is TREM number 130. In some embodiments, the TREM containing the LNA portion is TREM number 132. In some embodiments, the TREM containing the LNA portion is TREM number 133. In some embodiments, the TREM containing the LNA portion is TREM number 134. In some embodiments, the TREM containing the LNA portion is TREM number 135. In some embodiments, the TREM containing the LNA portion is TREM number 136. In some embodiments, the TREM containing the LNA portion is TREM number 137. In some embodiments, the TREM containing the LNA portion is TREM number 138. In some embodiments, the TREM containing the LNA portion is TREM number 139. In some embodiments, the TREM containing the LNA portion is TREM number 140. In some embodiments, the TREM containing the LNA portion is TREM number 141. In some embodiments, the TREM containing the LNA portion is TREM number 142. In some embodiments, the TREM containing the LNA portion is TREM number 143. In some embodiments, the TREM containing the LNA portion is TREM number 144. In some embodiments, the TREM containing the LNA portion is TREM number 145. In some embodiments, the TREM containing the LNA portion is TREM number 146.In some embodiments, the TREM containing the LNA portion is TREM number 147. In some embodiments, the TREM containing the LNA portion is TREM number 148. In some embodiments, the TREM containing the LNA portion is TREM number 149. In some embodiments, the TREM containing the LNA portion is TREM number 150. In some embodiments, the TREM containing the LNA portion is TREM number 151. In some embodiments, the TREM containing the LNA portion is TREM number 152. In some embodiments, the TREM containing the LNA portion is TREM number 153. In some embodiments, the TREM containing the LNA portion is TREM number 154. In some embodiments, the TREM containing the LNA portion is TREM number 155. In some embodiments, the TREM containing the LNA portion is TREM number 156. In some embodiments, the TREM containing the LNA portion is TREM number 157. In some embodiments, the TREM containing the LNA portion is TREM number 158. In some embodiments, the TREM containing the LNA portion is TREM number 159. In some embodiments, the TREM containing the LNA portion is TREM number 160. In some embodiments, the TREM containing the LNA portion is TREM number 161. In some embodiments, the TREM containing the LNA portion is TREM number 162. In some embodiments, the TREM containing the LNA portion is TREM number 163. In some embodiments, the TREM containing the LNA portion is TREM number 164. In some embodiments, the TREM containing the LNA portion is TREM number 165. In some embodiments, the TREM containing the LNA portion is TREM number 166.

[0285] In some embodiments, the TREM containing the LNA portion is TREM number 444. In some embodiments, the TREM containing the LNA portion is TREM number 445. In some embodiments, the TREM containing the LNA portion is TREM number 451. In some embodiments, the TREM containing the LNA portion is TREM number 454. In some embodiments, the TREM containing the LNA portion is TREM number 547. In some embodiments, the TREM containing the LNA portion is TREM number 566. In some embodiments, the TREM containing the LNA portion is TREM number 628.

[0286] 2',5'-linked nucleotides In one embodiment, this disclosure relates to formula (III): [ka] The TREM sequence consists of a 2',5'-linked nucleotide having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, where: B is a nucleic acid base; Y is C(R'), O, or N(R'). B ) and; R 1 , R 2 , and R 4 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 3a and R 3b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; R 10 However, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 but is hydrogen or a C1-C6 alkyl group; and x and y are independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0287] In some embodiments, B is a native nucleic acid base (e.g., adenine, cytosine, guanine, uracil). In some embodiments, B is a purine nucleic acid base; in some embodiments, B is a pyrimidine nucleic acid base. In some embodiments, B is adenine. In some embodiments, B is cytosine. In some embodiments, B is guanine. In some embodiments, B is uracil. In some embodiments, B is a non-native nucleic acid base.

[0288] In some embodiments, B includes chemical modifications (e.g., natural or unnatural chemical modifications). In some embodiments, the chemical modification is a nucleotide sugar modification, a nucleic acid base modification, or an internucleotide bond modification. In some embodiments, the chemical modification is a nucleotide sugar modification. In some embodiments, the chemical modification is a 2'OMe modification. In some embodiments, the chemical modification is a 2'halo (e.g., 2'F or 2'Cl) modification. In some embodiments, the chemical modification is a 2'MOE modification. In some embodiments, the chemical modification is a 2'-deoxy modification. In some embodiments, the chemical modification is located in an internucleotide region (e.g., a skeletal modification). In some embodiments, the chemical modification is a phosphorothioate modification.

[0289] In some embodiments, B does not contain any chemical modifications (e.g., natural or non-natural chemical modifications).

[0290] In some embodiments, Y is C(R'). In some embodiments, Y is O. In some embodiments, Y is N(R B )

[0291] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 1is hydrogen. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C6 alkenyl. In some embodiments, R 1 is a C2-C6 alkynyl. In some embodiments, R 1 R is a C1-C6 heteroalkyl. In some embodiments, R 1 R is a C1-C6 haloalkyl. In some embodiments, R 1 is a halo. In some embodiments, R 1 is cyano. In some embodiments, R 1 は-OR A In some embodiments, R 1 is -N(R B )(R C )

[0292] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 R is a C2-C6 alkenyl. In some embodiments, R 2 is a C2-C6 alkynyl. In some embodiments, R 2 R is a C1-C6 heteroalkyl. In some embodiments, R 2 R is a C1-C6 haloalkyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 is cyano. In some embodiments, R 2 は-OR A In some embodiments, R 2 is -N(R B )(R C )

[0293] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 4 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 R is a C2-C6 alkenyl. In some embodiments, R 4 is a C2-C6 alkynyl. In some embodiments, R 4 R is a C1-C6 heteroalkyl. In some embodiments, R 4 R is a C1-C6 haloalkyl. In some embodiments, R 4 is a halo. In some embodiments, R 4 is cyano. In some embodiments, R 4 は-OR A In some embodiments, R 4 is -N(R B )(R C )

[0294] In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 3a and R 3b One of them is hydrogen, independently. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 3a and R 3bOne of these is, independently, a C2-C6 alkenyl. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b One of them is, independently, a halo. In some embodiments, R 3a and R 3b One of them is independently cyano. In some embodiments, R 3a and R 3b One of them is independently, -OR A In some embodiments, R 3a and R 3b One of them is independently -N(R B )(R C )

[0295] In some embodiments, R 3a and R 3b Each of them is independently hydrogen. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3bEach of these is independently a halo. In some embodiments, R 3a and R 3b Each of them is independently cyano. In some embodiments, R 3a and R 3b Each of these independently, -OR A In some embodiments, R 3a and R 3b Each of these independently, -N(R B )(R C )

[0296] In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 5a and R 5b One of them is hydrogen, independently. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b One of them is, independently, a halo. In some embodiments, R 5a and R 5b One of them is independently cyano. In some embodiments, R 5aand R 5b One of them is independently, -OR A In some embodiments, R 5a and R 5b One of them is independently -N(R B )(R C )

[0297] In some embodiments, R 5a and R 5b Each of them is independently hydrogen. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b Each of these is independently a halo. In some embodiments, R 5a and R 5b Each of them is independently cyano. In some embodiments, R 5a and R 5b Each of these independently, -OR A In some embodiments, R 5a and R 5b Each of these independently, -N(R B )(R C )

[0298] In some embodiments, R' is hydrogen. In some embodiments, R' is a C1-C6 alkyl group.

[0299] Several embodiments, each R A These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 heteroalkyl. In some embodiments, each R A R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, each R A R is independently hydrogen or a C1-C6 alkyl group. In some embodiments, each R A It is, independently, hydrogen.

[0300] In some embodiments, R B and R C Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R B and R C Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R B and R C Each of them is, independently, hydrogen.

[0301] In some embodiments, R 10 This refers to C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 In some embodiments, R 10 is a C1-C6 alkyl, a C1-C6 heteroalkyl, or a C1-C6 haloalkyl. In some embodiments, R 10 is a C1-C6 alkyl or C1-C6 heteroalkyl. In some embodiments, R 10 is a C1-C6 alkyl group. In some embodiments, R 10 R is a C1-C6 heteroalkyl. In some embodiments, R 10 R is a C1-C6 haloalkyl. In some embodiments, R 10 is a halo. In some embodiments, R 10 is cyano. In some embodiments, R 10 は-OR A1 That is the case.

[0302] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 These are C1-C6 alkyl groups.

[0303] In some embodiments, x and y are independently 0, 1, or 2; in some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0304] In some embodiments, the TREM comprises a single 2',5'-linked nucleotide. In some embodiments, the TREM comprises multiple 2',5'-linked nucleotides. In some embodiments, the TREM comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 2',5'-linked nucleotides.

[0305] In some embodiments, the 2',5'-binding nucleotide is located in [L1]-[ASt domain 1]-[L2]. In some embodiments, the 2',5'-binding nucleotide is located in [L1]-[ASt domain 1]-[L2]. In some embodiments, the 2',5'-binding nucleotide is located in [L2]-[DH domain]-[L3]. In some embodiments, the 2',5'-binding nucleotide is located in [L3]-[ACH domain]. In some embodiments, the 2',5'-binding nucleotide is located in the [VL domain]. In some embodiments, the 2',5'-binding nucleotide is located in the [TH domain]. In some embodiments, the 2',5'-binding nucleotide is located in [L4]-[ASt domain 2]-[L5].

[0306] In some embodiments, the TREM has an array selected from the arrays provided in Figure 1.

[0307] In some embodiments, the TREM includes a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with the TREMs provided in Table 1.

[0308] In some embodiments, the TREM includes a nucleotide sequence that differs from any one of the TREMs provided in Table 1, for example, any one of the TREMs having SEQ ID NOs. 794-991, 1060, 1062, 1112, 1135, 1153-1158, 1161, 1163, 1166-1170, 1175, 1200, 1207, and 1253-1415 (for example, any one of the TREMs having SEQ ID NOs. 794-991, for example, any one of the TREMs having SEQ ID NOs. 1060, 1062, 1112, 1135, 1153-1158, 1161, 1163, 1166-1170, 1175, 1200, 1207, and 1253-1415) by only 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer nucleotides.

[0309] In some embodiments, the TREM includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-natural modifications (e.g., 2'-ribose modifications or internucleotide modifications, e.g., 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothiolate modifications) compared to the TREMs provided in Table 1. In some embodiments, the TREM includes any one of the TREMs having SEQ ID NOs. 794-991, 1060, 1062, 1112, 1135, 1153-1158, 1161, 1163, 1166-1170, 1175, 1200, 1207, or 1253-1415 (e.g., any one of the nucleotide sequences of the TREMs having SEQ ID NOs. 794-991).

[0310] In one embodiment, this disclosure is given by formula (III-a): [ka] The TREM sequence consists of a 2',5'-linked nucleotide having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, where: B is a nucleic acid base; Y is C(R'), O, or N(R'). B ) and; R 1 , R 2 , and R 4 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 3a However, hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 3c is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R AHowever, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; R 10 However, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 but is hydrogen or a C1-C6 alkyl group; and x and y are independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0311] In some embodiments, B is a native nucleic acid base (e.g., adenine, cytosine, guanine, uracil). In some embodiments, B is a non-native nucleic acid base.

[0312] In some embodiments, B includes chemical modifications (e.g., natural or unnatural chemical modifications). In some embodiments, the chemical modification is a nucleotide sugar modification, a nucleic acid base modification, or an internucleotide bond modification. In some embodiments, the chemical modification is a nucleotide sugar modification. In some embodiments, the chemical modification is a 2'OMe modification. In some embodiments, the chemical modification is a 2'halo (e.g., 2'F or 2'Cl) modification. In some embodiments, the chemical modification is a 2'MOE modification. In some embodiments, the chemical modification is a 2'-deoxy modification. In some embodiments, the chemical modification is located in an internucleotide region (e.g., a skeletal modification). In some embodiments, the chemical modification is a phosphorothioate modification.

[0313] In some embodiments, B does not contain any chemical modifications (e.g., natural or non-natural chemical modifications).

[0314] In some embodiments, Y is C(R'). In some embodiments, Y is O. In some embodiments, Y is N(R B )

[0315] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C6 alkenyl. In some embodiments, R 1 is a C2-C6 alkynyl. In some embodiments, R 1 R is a C1-C6 heteroalkyl. In some embodiments, R 1 R is a C1-C6 haloalkyl. In some embodiments, R 1 is a halo. In some embodiments, R1 is cyano. In some embodiments, R 1 は-OR A In some embodiments, R 1 is -N(R B )(R C )

[0316] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 R is a C2-C6 alkenyl. In some embodiments, R 2 is a C2-C6 alkynyl. In some embodiments, R 2 R is a C1-C6 heteroalkyl. In some embodiments, R 2 R is a C1-C6 haloalkyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 is cyano. In some embodiments, R 2 は-OR A In some embodiments, R 2 is -N(R B )(R C )

[0317] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 4 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4R is a C2-C6 alkenyl. In some embodiments, R 4 is a C2-C6 alkynyl. In some embodiments, R 4 R is a C1-C6 heteroalkyl. In some embodiments, R 4 R is a C1-C6 haloalkyl. In some embodiments, R 4 is a halo. In some embodiments, R 4 is cyano. In some embodiments, R 4 は-OR A In some embodiments, R 4 is -N(R B )(R C )

[0318] In some embodiments, R 3a R is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 3a R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 3a is hydrogen. In some embodiments, R 3a is a C1-C6 alkyl group. In some embodiments, R 3a R is a C2-C6 alkenyl. In some embodiments, R 3a is a C2-C6 alkynyl. In some embodiments, R 3a R is a C1-C6 heteroalkyl. In some embodiments, R 3a R is a C1-C6 haloalkyl. In some embodiments, R 3a is a halo. In some embodiments, R 3a is cyano. In some embodiments, R 3a は-OR A In some embodiments, R 3a is -N(R B )(R C )

[0319] In some embodiments, R 3cis hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 It is optionally replaced by R. In some embodiments, 3c R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 3c is hydrogen. In some embodiments, R 3c is a C1-C6 alkyl group. In some embodiments, R 3c It is a C1-C6 heteroalkyl group.

[0320] In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 5a and R 5b One of them is hydrogen, independently. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b One of them is, independently, a halo. In some embodiments, R5a and R 5b One of them is independently cyano. In some embodiments, R 5a and R 5b One of them is independently, -OR A In some embodiments, R 5a and R 5b One of them is independently -N(R B )(R C )

[0321] In some embodiments, R 5a and R 5b Each of them is independently hydrogen. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b Each of these is independently a halo. In some embodiments, R 5a and R 5b Each of them is independently cyano. In some embodiments, R 5a and R 5b Each of these independently, -OR A In some embodiments, R 5a and R 5b Each of these independently, -N(R B )(R C )

[0322] In some embodiments, R' is hydrogen. In some embodiments, R' is a C1-C6 alkyl group.

[0323] Several embodiments, each R A These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 heteroalkyl. In some embodiments, each R A R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, each R A R is independently hydrogen or a C1-C6 alkyl group. In some embodiments, each R A It is, independently, hydrogen.

[0324] In some embodiments, R B and R C Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R B and R C Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R B and R C Each of them is, independently, hydrogen.

[0325] In some embodiments, R 10 This refers to C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 In some embodiments, R 10 is a C1-C6 alkyl, a C1-C6 heteroalkyl, or a C1-C6 haloalkyl. In some embodiments, R 10 is a C1-C6 alkyl or C1-C6 heteroalkyl. In some embodiments, R 10 is a C1-C6 alkyl group. In some embodiments, R 10 R is a C1-C6 heteroalkyl. In some embodiments, R 10 R is a C1-C6 haloalkyl. In some embodiments, R 10is a halo. In some embodiments, R 10 is cyano. In some embodiments, R 10 は-OR A1 That is the case.

[0326] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 These are C1-C6 alkyl groups.

[0327] In some embodiments, x and y are independently 0, 1, or 2; in some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0328] In some embodiments, the nucleotides in the TREM sequence containing 2',5'-linked nucleotides are of formula (III-ai) or formula (III-a-ii): [ka] It has the structure of a salt, stereoisomer, tautomer, or hydrate thereof.

[0329] In one embodiment, this disclosure relates to formula (III-b): [ka] The TREM sequence consists of a 2',5'-linked nucleotide having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, where Y is C(R'), O, or N(R B ) and; R 1 , R 2 , and R 4 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(RC ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 3a and R 3b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; R 10 However, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1However, it is hydrogen or C1-C6 alkyl; R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, or a C1-C6 haloalkyl group; R ii and R iii Each of them is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo; each of x and y is independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0330] In some embodiments, Y is C(R'). In some embodiments, Y is O. In some embodiments, Y is N(R B )

[0331] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C6 alkenyl. In some embodiments, R 1 is a C2-C6 alkynyl. In some embodiments, R 1 R is a C1-C6 heteroalkyl. In some embodiments, R 1 R is a C1-C6 haloalkyl. In some embodiments, R 1 is a halo. In some embodiments, R 1 is cyano. In some embodiments, R 1 は-OR A In some embodiments, R 1 is -N(RB )(R C )

[0332] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 R is a C2-C6 alkenyl. In some embodiments, R 2 is a C2-C6 alkynyl. In some embodiments, R 2 R is a C1-C6 heteroalkyl. In some embodiments, R 2 R is a C1-C6 haloalkyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 is cyano. In some embodiments, R 2 は-OR A In some embodiments, R 2 is -N(R B )(R C )

[0333] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 4 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 R is a C2-C6 alkenyl. In some embodiments, R 4 is a C2-C6 alkynyl. In some embodiments, R 4R is a C1-C6 heteroalkyl. In some embodiments, R 4 R is a C1-C6 haloalkyl. In some embodiments, R 4 is a halo. In some embodiments, R 4 is cyano. In some embodiments, R 4 は-OR A In some embodiments, R 4 is -N(R B )(R C )

[0334] In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 3a and R 3b One of them is hydrogen, independently. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b One of them is, independently, a halo. In some embodiments, R 3a and R 3b One of them is independently cyano. In some embodiments, R 3a and R3b One of them is independently, -OR A In some embodiments, R 3a and R 3b One of them is independently -N(R B )(R C )

[0335] In some embodiments, R 3a and R 3b Each of them is independently hydrogen. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b Each of these is independently a halo. In some embodiments, R 3a and R 3b Each of them is independently cyano. In some embodiments, R 3a and R 3b Each of these independently, -OR A In some embodiments, R 3a and R 3b Each of these independently, -N(R B )(R C )

[0336] In some embodiments, R 5a and R 5bEach of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 5a and R 5b One of them is hydrogen, independently. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b One of them is, independently, a halo. In some embodiments, R 5a and R 5b One of them is independently cyano. In some embodiments, R 5a and R 5b One of them is independently, -OR A In some embodiments, R 5a and R 5b One of them is independently -N(R B )(R C )

[0337] In some embodiments, R 5a and R 5b Each of them is independently hydrogen. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 alkyl group. In some embodiments, R5a and R 5b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b Each of these is independently a halo. In some embodiments, R 5a and R 5b Each of them is independently cyano. In some embodiments, R 5a and R 5b Each of these independently, -OR A In some embodiments, R 5a and R 5b Each of these independently, -N(R B )(R C )

[0338] In some embodiments, R' is hydrogen. In some embodiments, R' is a C1-C6 alkyl group.

[0339] Several embodiments, each R A These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 heteroalkyl. In some embodiments, each R A R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, each R A R is independently hydrogen or a C1-C6 alkyl group. In some embodiments, each R A It is, independently, hydrogen.

[0340] In some embodiments, R B and R CEach of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R B and R C Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R B and R C Each of them is, independently, hydrogen.

[0341] In some embodiments, R 10 This refers to C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 In some embodiments, R 10 is a C1-C6 alkyl, a C1-C6 heteroalkyl, or a C1-C6 haloalkyl. In some embodiments, R 10 is a C1-C6 alkyl or C1-C6 heteroalkyl. In some embodiments, R 10 is a C1-C6 alkyl group. In some embodiments, R 10 R is a C1-C6 heteroalkyl. In some embodiments, R 10 R is a C1-C6 haloalkyl. In some embodiments, R 10 is a halo. In some embodiments, R 10 is cyano. In some embodiments, R 10 は-OR A1 That is the case.

[0342] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 These are C1-C6 alkyl groups.

[0343] In some embodiments, R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R ia and R ib Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R ia and Rib Each of them is, independently, hydrogen.

[0344] In some embodiments, R ii and R iii Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R ii and R iii Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R ii and R iii Each of them is, independently, hydrogen.

[0345] In some embodiments, x and y are independently 0, 1, or 2; in some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0346] In another aspect, this disclosure relates to formula (III-c): [ka] The TREM sequence consists of a 2',5'-linked nucleotide having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, where Y is C(R'), O, or N(R B ) and; R 1 , R 2 , and R 4 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 3a and R 3bEach of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; R 10 However, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 However, it is hydrogen or C1-C6 alkyl; R ia and R ib Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl; R iiHowever, it is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl; R iii is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo; x and y are independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0347] In some embodiments, Y is C(R'). In some embodiments, Y is O. In some embodiments, Y is N(R B )

[0348] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C6 alkenyl. In some embodiments, R 1 is a C2-C6 alkynyl. In some embodiments, R 1 R is a C1-C6 heteroalkyl. In some embodiments, R 1 R is a C1-C6 haloalkyl. In some embodiments, R 1 is a halo. In some embodiments, R 1 is cyano. In some embodiments, R 1 は-OR A In some embodiments, R 1 is -N(R B )(R C )

[0349] In some embodiments, R2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 R is a C2-C6 alkenyl. In some embodiments, R 2 is a C2-C6 alkynyl. In some embodiments, R 2 R is a C1-C6 heteroalkyl. In some embodiments, R 2 R is a C1-C6 haloalkyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 is cyano. In some embodiments, R 2 は-OR A In some embodiments, R 2 is -N(R B )(R C )

[0350] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 4 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 R is a C2-C6 alkenyl. In some embodiments, R 4 is a C2-C6 alkynyl. In some embodiments, R 4 R is a C1-C6 heteroalkyl. In some embodiments, R 4 R is a C1-C6 haloalkyl. In some embodiments, R 4 is a halo. In some embodiments, R4 is cyano. In some embodiments, R 4 は-OR A In some embodiments, R 4 is -N(R B )(R C )

[0351] In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 3a and R 3b One of them is hydrogen, independently. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b One of them is, independently, a halo. In some embodiments, R 3a and R 3b One of them is independently cyano. In some embodiments, R 3a and R 3b One of them is independently, -OR A In some embodiments, R 3a and R 3b One of them is independently -N(R B)(R C )

[0352] In some embodiments, R 3a and R 3b Each of them is independently hydrogen. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b Each of these is independently a halo. In some embodiments, R 3a and R 3b Each of them is independently cyano. In some embodiments, R 3a and R 3b Each of these independently, -OR A In some embodiments, R 3a and R 3b Each of these independently, -N(R B )(R C )

[0353] In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 5aand R 5b One of them is hydrogen, independently. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b One of them is, independently, a halo. In some embodiments, R 5a and R 5b One of them is independently cyano. In some embodiments, R 5a and R 5b One of them is independently, -OR A In some embodiments, R 5a and R 5b One of them is independently -N(R B )(R C )

[0354] In some embodiments, R 5a and R 5b Each of them is independently hydrogen. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 5a and R 5bEach of these is independently a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b Each of these is independently a halo. In some embodiments, R 5a and R 5b Each of them is independently cyano. In some embodiments, R 5a and R 5b Each of these independently, -OR A In some embodiments, R 5a and R 5b Each of these independently, -N(R B )(R C )

[0355] In some embodiments, R' is hydrogen. In some embodiments, R' is a C1-C6 alkyl group.

[0356] Several embodiments, each R A These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 heteroalkyl. In some embodiments, each R A R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, each R A R is independently hydrogen or a C1-C6 alkyl group. In some embodiments, each R A It is, independently, hydrogen.

[0357] In some embodiments, R B and R C Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R B and R C Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R B and R CEach of them is, independently, hydrogen.

[0358] In some embodiments, R 10 This refers to C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 In some embodiments, R 10 is a C1-C6 alkyl, a C1-C6 heteroalkyl, or a C1-C6 haloalkyl. In some embodiments, R 10 is a C1-C6 alkyl or C1-C6 heteroalkyl. In some embodiments, R 10 is a C1-C6 alkyl group. In some embodiments, R 10 R is a C1-C6 heteroalkyl. In some embodiments, R 10 R is a C1-C6 haloalkyl. In some embodiments, R 10 is a halo. In some embodiments, R 10 is cyano. In some embodiments, R 10 は-OR A1 That is the case.

[0359] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 These are C1-C6 alkyl groups.

[0360] In some embodiments, R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R ia and R ib Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R ia and R ib Each of them is, independently, hydrogen.

[0361] In some embodiments, R ii R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R iiis hydrogen or a C1-C6 alkyl group. In some embodiments, R ii It is hydrogen.

[0362] In some embodiments, R iii R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R iii is hydrogen or a C1-C6 alkyl group. In some embodiments, R iii It is hydrogen.

[0363] In some embodiments, x and y are independently 0, 1, or 2; in some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0364] In another aspect, this disclosure relates to formula (III-d): [ka] The TREM sequence consists of a 2',5'-linked nucleotide having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, where Y is C(R'), O, or N(R B ) and; R 1 , R 2 , and R 4 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 3a and R 3bEach of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; R 10 However, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 However, it is hydrogen or C1-C6 alkyl; R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, a C1-C6 heteroalkyl group, or a C1-C6 haloalkyl group; R ii and R iiiEach of them is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo; each of x and y is independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0365] In some embodiments, Y is C(R'). In some embodiments, Y is O. In some embodiments, Y is N(R B )

[0366] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C6 alkenyl. In some embodiments, R 1 is a C2-C6 alkynyl. In some embodiments, R 1 R is a C1-C6 heteroalkyl. In some embodiments, R 1 R is a C1-C6 haloalkyl. In some embodiments, R 1 is a halo. In some embodiments, R 1 is cyano. In some embodiments, R 1 は-OR A In some embodiments, R 1 is -N(R B )(R C )

[0367] In some embodiments, R 2R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 R is a C2-C6 alkenyl. In some embodiments, R 2 is a C2-C6 alkynyl. In some embodiments, R 2 R is a C1-C6 heteroalkyl. In some embodiments, R 2 R is a C1-C6 haloalkyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 is cyano. In some embodiments, R 2 は-OR A In some embodiments, R 2 is -N(R B )(R C )

[0368] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 4 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 R is a C2-C6 alkenyl. In some embodiments, R 4 is a C2-C6 alkynyl. In some embodiments, R 4 R is a C1-C6 heteroalkyl. In some embodiments, R 4 R is a C1-C6 haloalkyl. In some embodiments, R 4 is a halo. In some embodiments, R 4is cyano. In some embodiments, R 4 は-OR A In some embodiments, R 4 is -N(R B )(R C )

[0369] In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 3a and R 3b One of them is hydrogen, independently. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b One of them is, independently, a halo. In some embodiments, R 3a and R 3b One of them is independently cyano. In some embodiments, R 3a and R 3b One of them is independently, -OR A In some embodiments, R 3a and R 3b One of them is independently -N(R B )(RC )

[0370] In some embodiments, R 3a and R 3b Each of them is independently hydrogen. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b Each of these is independently a halo. In some embodiments, R 3a and R 3b Each of them is independently cyano. In some embodiments, R 3a and R 3b Each of these independently, -OR A In some embodiments, R 3a and R 3b Each of these independently, -N(R B )(R C )

[0371] In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 5a and R5b One of them is hydrogen, independently. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b One of them is, independently, a halo. In some embodiments, R 5a and R 5b One of them is independently cyano. In some embodiments, R 5a and R 5b One of them is independently, -OR A In some embodiments, R 5a and R 5b One of them is independently -N(R B )(R C )

[0372] In some embodiments, R 5a and R 5b Each of them is independently hydrogen. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 5a and R 5bEach of these is independently a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b Each of these is independently a halo. In some embodiments, R 5a and R 5b Each of them is independently cyano. In some embodiments, R 5a and R 5b Each of these independently, -OR A In some embodiments, R 5a and R 5b Each of these independently, -N(R B )(R C )

[0373] In some embodiments, R' is hydrogen. In some embodiments, R' is a C1-C6 alkyl group.

[0374] Several embodiments, each R A These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 heteroalkyl. In some embodiments, each R A R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, each R A R is independently hydrogen or a C1-C6 alkyl group. In some embodiments, each R A It is, independently, hydrogen.

[0375] In some embodiments, R B and R C Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R B and R C Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R B and R CEach of them is, independently, hydrogen.

[0376] In some embodiments, R 10 This refers to C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 In some embodiments, R 10 is a C1-C6 alkyl, a C1-C6 heteroalkyl, or a C1-C6 haloalkyl. In some embodiments, R 10 is a C1-C6 alkyl or C1-C6 heteroalkyl. In some embodiments, R 10 is a C1-C6 alkyl group. In some embodiments, R 10 R is a C1-C6 heteroalkyl. In some embodiments, R 10 R is a C1-C6 haloalkyl. In some embodiments, R 10 is a halo. In some embodiments, R 10 is cyano. In some embodiments, R 10 は-OR A1 That is the case.

[0377] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 These are C1-C6 alkyl groups.

[0378] In some embodiments, R ia and R ib Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R ia and R ib Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R ia and R ib Each of them is, independently, hydrogen.

[0379] In some embodiments, R ii and R iiiEach of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R ii and R iii Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R ii and R iii Each of them is, independently, hydrogen.

[0380] In some embodiments, x and y are independently 0, 1, or 2; in some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0381] In another aspect, this disclosure relates to formula (III-e): [ka] The TREM sequence consists of a 2',5'-linked nucleotide having the structure of a salt, stereoisomer, tautomer, or hydrate thereof, where Y is C(R'), O, or N(R B ) and; R 1 , R 2 , and R 4 Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 3a and R 3b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(RC ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 Replaced by optional selection; R 5a and R 5b Each of these can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -OR A , or -N(R B )(R C ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R 10 R' is optionally substituted; R' is hydrogen or a C1-C6 alkyl group; each R A However, independently, these are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R B and R C Each of them independently is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocyclyl; or R B and R C However, together with the atom to which they are bonded, one or more R 11 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; R 10 However, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1 And; R A1 However, it is hydrogen or C1-C6 alkyl; R i However, it is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl; R ii and R iii Each of them is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo; each of x and y is independently 0, 1, or 2; [ka] However, this refers to the remaining part of the TREM sequence, another atom, or a bond point to the end of the TREM.

[0382] In some embodiments, Y is C(R'). In some embodiments, Y is O. In some embodiments, Y is N(R B )

[0383] In some embodiments, R 1 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 1 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C6 alkenyl. In some embodiments, R 1 is a C2-C6 alkynyl. In some embodiments, R 1 R is a C1-C6 heteroalkyl. In some embodiments, R 1 R is a C1-C6 haloalkyl. In some embodiments, R 1 is a halo. In some embodiments, R 1 is cyano. In some embodiments, R 1 は-OR A In some embodiments, R 1 is -N(R B )(R C )

[0384] In some embodiments, R 2 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 2 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 2 is hydrogen. In some embodiments, R 2is a C1-C6 alkyl group. In some embodiments, R 2 R is a C2-C6 alkenyl. In some embodiments, R 2 is a C2-C6 alkynyl. In some embodiments, R 2 R is a C1-C6 heteroalkyl. In some embodiments, R 2 R is a C1-C6 haloalkyl. In some embodiments, R 2 is a halo. In some embodiments, R 2 is cyano. In some embodiments, R 2 は-OR A In some embodiments, R 2 is -N(R B )(R C )

[0385] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, or halo. In some embodiments, R 4 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 R is a C2-C6 alkenyl. In some embodiments, R 4 is a C2-C6 alkynyl. In some embodiments, R 4 R is a C1-C6 heteroalkyl. In some embodiments, R 4 R is a C1-C6 haloalkyl. In some embodiments, R 4 is a halo. In some embodiments, R 4 is cyano. In some embodiments, R 4 は-OR A In some embodiments, R 4 is -N(R B )(R C )

[0386] In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 3a and R 3b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 3a and R 3b One of them is hydrogen, independently. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkenyl. In some embodiments, R 3a and R 3b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 3a and R 3b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b One of them is, independently, a halo. In some embodiments, R 3a and R 3b One of them is independently cyano. In some embodiments, R 3a and R 3b One of them is independently, -OR A In some embodiments, R 3a and R 3b One of them is independently -N(R B )(R C )

[0387] In some embodiments, R 3a and R 3b Each of them is independently hydrogen. In some embodiments, R 3a and R 3bEach of these is independently a C1-C6 alkyl group. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 3a and R 3b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 3a and R 3b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 3a and R 3b Each of these is independently a halo. In some embodiments, R 3a and R 3b Each of them is independently cyano. In some embodiments, R 3a and R 3b Each of these independently, -OR A In some embodiments, R 3a and R 3b Each of these independently, -N(R B )(R C )

[0388] In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 heteroalkyl, a C1-C6 haloalkyl, or a halo. In some embodiments, R 5a and R 5b Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R 5a and R 5b One of them is hydrogen, independently. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 alkyl group. In some embodiments, R 5a and R 5bOne of these is, independently, a C2-C6 alkenyl. In some embodiments, R 5a and R 5b One of these is, independently, a C2-C6 alkynyl. In some embodiments, R 5a and R 5b One of them is, independently, a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b One of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5b One of them is, independently, a halo. In some embodiments, R 5a and R 5b One of them is independently cyano. In some embodiments, R 5a and R 5b One of them is independently, -OR A In some embodiments, R 5a and R 5b One of them is independently -N(R B )(R C )

[0389] In some embodiments, R 5a and R 5b Each of them is independently hydrogen. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 alkyl group. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkenyl. In some embodiments, R 5a and R 5b Each of these is independently a C2-C6 alkynyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 heteroalkyl. In some embodiments, R 5a and R 5b Each of these is independently a C1-C6 haloalkyl. In some embodiments, R 5a and R 5bEach of these is independently a halo. In some embodiments, R 5a and R 5b Each of them is independently cyano. In some embodiments, R 5a and R 5b Each of these independently, -OR A In some embodiments, R 5a and R 5b Each of these independently, -N(R B )(R C )

[0390] In some embodiments, R' is hydrogen. In some embodiments, R' is a C1-C6 alkyl group.

[0391] Several embodiments, each R A These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 heteroalkyl. In some embodiments, each R A R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, each R A R is independently hydrogen or a C1-C6 alkyl group. In some embodiments, each R A It is, independently, hydrogen.

[0392] In some embodiments, R B and R C Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R B and R C Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R B and R C Each of them is, independently, hydrogen.

[0393] In some embodiments, R 10 This refers to C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A1In some embodiments, R 10 is a C1-C6 alkyl, a C1-C6 heteroalkyl, or a C1-C6 haloalkyl. In some embodiments, R 10 is a C1-C6 alkyl or C1-C6 heteroalkyl. In some embodiments, R 10 is a C1-C6 alkyl group. In some embodiments, R 10 R is a C1-C6 heteroalkyl. In some embodiments, R 10 R is a C1-C6 haloalkyl. In some embodiments, R 10 is a halo. In some embodiments, R 10 is cyano. In some embodiments, R 10 は-OR A1 That is the case.

[0394] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 These are C1-C6 alkyl groups.

[0395] In some embodiments, R i R is hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R i is hydrogen or a C1-C6 alkyl group. In some embodiments, R i It is hydrogen.

[0396] In some embodiments, R ii and R iii Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 heteroalkyl group. In some embodiments, R ii and R iii Each of these is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R ii and R iii Each of them is, independently, hydrogen.

[0397] In some embodiments, x and y are independently 0, 1, or 2; in some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2.

[0398] In some embodiments, the diseases or disorders associated with PTC include hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease.

[0399] TREM may contain multiple 2',5'-binding nucleotides independently located within [ASt domain 1], [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2]. In some embodiments, TREM contains one 2',5'-binding nucleotide. In some embodiments, TREM contains a 2',5'-binding nucleotide located in [ASt domain 1]. In some embodiments, TREM contains a 2',5'-binding nucleotide located in the [DH domain]. In some embodiments, TREM contains a 2',5'-binding nucleotide located in the [ACH domain]. In some embodiments, TREM contains a 2',5'-binding nucleotide located in the [VL domain]. In some embodiments, TREM contains a 2',5'-binding nucleotide located in the [TH domain]. In some embodiments, TREM contains a 2',5'-binding nucleotide located in the [Ast2 domain].

[0400] In one embodiment, the 2',5'-linked nucleotides are located at nucleotide positions 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 of the TREM. In another embodiment, the 2',5'-linked nucleotides are located at nucleotide positions 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 of the TREM. In another embodiment, the TREM contains two or more 2',5'-linked nucleotides. In one embodiment, TREM contains two 2',5'-binding nucleotides. In one embodiment, TREM contains two 2',5'-binding nucleotides independently located in [ASt domain 1], [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2]. In one embodiment, TREM contains two 2',5'-binding nucleotides independently located in [ACH domain]. In one embodiment, TREM contains two 2',5'-binding nucleotides independently located in [DH domain]. In one embodiment, TREM contains two 2',5'-binding nucleotides independently located in [DH domain] and [TH domain]. In one embodiment, TREM contains two 2',5'-binding nucleotides independently located in [TH domain]. In one embodiment, TREM contains two 2',5'-binding nucleotides independently located in [ASt domain 1].

[0401] In one embodiment, TREM contains two 2',5'-joint nucleotides located independently between nucleotide positions 30 and 40. In one embodiment, TREM contains two 2',5'-joint nucleotides located independently between nucleotide positions 12 and 25. In one embodiment, TREM contains two 2',5'-joint nucleotides located independently between nucleotide positions 30 and 40. In one embodiment, TREM contains two 2',5'-joint nucleotides located at nucleotide positions 31 and 32. In one embodiment, TREM contains two 2',5'-joint nucleotides located at nucleotide positions 31 and 34. In one embodiment, TREM contains two 2',5'-joint nucleotides located at nucleotide positions 31 and 35. In one embodiment, TREM contains two 2',5'-joint nucleotides located at nucleotide positions 31 and 37. In one embodiment, TREM contains two 2',5'-joint nucleotides located at nucleotide positions 32 and 34.

[0402] TREM may contain three 2',5'-joint nucleotides. In one embodiment, TREM contains three 2',5'-joint nucleotides independently located in [ASt domain 1], [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2]. In another embodiment, TREM contains three 2',5'-joint nucleotides independently located between nucleotide positions 9 and 60.

[0403] A TREM may contain four 2',5'-binding nucleotides. In one embodiment, the TREM contains four 2',5'-binding nucleotides independently located in [ASt domain 1], [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2]. A TREM may contain five 2',5'-binding nucleotides. In one embodiment, the TREM contains five 2',5'-binding nucleotides independently located in [ASt domain 1], [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2]. A TREM may contain six 2',5'-binding nucleotides. In one embodiment, the TREM contains six 2',5'-binding nucleotides independently located in [ASt domain 1], [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2].

[0404] In one embodiment, TREM contains a 2',5'-linked nucleotide at nucleotide position 49.

[0405] TREM may contain several non-native modifications in addition to 2',5'-linked nucleotides. TREM may contain non-native modifications in each of the [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2]. In some embodiments, TREM contains four 2',5'-linked nucleotides independently located in the [ACH domain], [VL domain], [TH domain], and [ASt domain 2]. In some embodiments, TREM contains four 2',5'-linked nucleotides independently located at nucleotide positions 43, 45, 54, and 65.

[0406] In one embodiment, the TREM contains 24 2'-O-methyl modifications in addition to 5 2',5'-linked nucleotides. In another embodiment, the TREM contains 14 2'-fluoro modifications in addition to 5 2',5'-linked nucleotides. In yet another embodiment, the TREM contains 1 2'-O-methoxyethyl modification in addition to 5 loc nucleic acids. In yet another embodiment, the TREM contains 9 phosphorothioate modifications in addition to 5 loc nucleic acids. In some embodiments, TREM comprises five lock nucleic acids independently located in the [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2], 24 2'-O-methyl modifications independently located in the [ASt domain 1], [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2], 14 2'-fluoro modifications independently located in the [DH domain], [ACH domain], [VL domain], [TH domain], and [ASt domain 2], one 2'-O-methoxyethyl modification independently located in the [ACH domain], and nine phosphorothioate modifications independently located in the [ASt domain 1], [DH domain], [ACH domain], [TH domain], and [ASt domain 2].

[0407] In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 176. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 193. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 202. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 204. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 207. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 216. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 217. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 218. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 219. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 220. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 222. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 224. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 226. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 227. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 228. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 229. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 232. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 233. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 238. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 239.In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 240. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 241. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 242. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 243. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 244. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 245. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 246. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 247. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 248. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 249. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 250. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 251. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 252. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 253. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 254. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 255. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 256. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 257. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 258. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 259.In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 260. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 262. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 263. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 264. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 265. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 266. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 267. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 269. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 270. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 272. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 273. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 274. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 275. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 276. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 277. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 278. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 279. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 281. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 282. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 283.In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 284. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 285. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 286. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 287. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 288. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 289. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 290. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 291. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 292. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 293. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 294. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 295. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 296. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 297. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 298. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 299. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 301. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 302. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 304. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 305.In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 307. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 309. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 310. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 311. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 312. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 313. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 315. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 316. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 317. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 318. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 320. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 321. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 322. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 323. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 324. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 325. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 326. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 327. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 328. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 329.In some embodiments, the TREM containing a 2',5'-linked nucleotide is TREM number 330. In some embodiments, the TREM containing a 2',5'-linked nucleotide is TREM number 331. In some embodiments, the 2',5'-linked nucleotide is... A TREM containing a nucleotide is designated TREM number 332. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 333. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 334. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 335. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 336. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 337. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 338. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 339. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 340. In some embodiments, a TREM containing a 2',5'-linked nucleotide is designated TREM number 341. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 342. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 343. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 346. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 357. In some embodiments, the TREM containing the 2',5'-linked nucleotide is TREM number 361.

[0408] TREM containing additional modifications A TREM comprising a lock nucleic acid moiety or a 2',5'-linked nucleotide and at least one additional non-natural modification is described herein. In one embodiment, the TREM comprises a lock nucleic acid moiety and a 2',5'-linked nucleotide. In another embodiment, the TREM comprises a lock nucleic acid moiety and a 2',5'-linked nucleotide, as well as an additional non-natural modification.

[0409] In some embodiments, the TREM comprises one LNA moiety or 2',5'-linked nucleotide. In some embodiments, the TREM comprises multiple LNA moieties and 2',5'-linked nucleotides. In some embodiments, the TREM comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 LNA moieties or 2',5'-linked nucleotides. In some embodiments, the TREM comprises at least one LNA moiety and at least one 2',5'-linked nucleotide. In some embodiments, the TREM comprises one LNA moiety and one 2',5'-linked nucleotide. In some embodiments, the TREM comprising the LNA moiety and the 2',5'-linked nucleotide is a TREM having one of the following sequence numbers: 1060, 1062, 1112, 1135, 1153-1158, 1161, 1163, 1166-1170, 1175, 1200, 1207, 1357, 1364, 1378-1393, and 1397-1398.

[0410] In some embodiments, the TREM comprises two LNA moieties and at least one 2',5'-linked nucleotide. In some embodiments, the TREM comprises two LNA moieties and one 2',5'-linked nucleotide. In some embodiments, the TREM comprises two LNA moieties and two 2',5'-linked nucleotides. In some embodiments, the TREM comprises two LNA moieties and three 2',5'-linked nucleotides. In some embodiments, the TREM comprises two LNA moieties and four 2',5'-linked nucleotides.

[0411] In some embodiments, the TREM comprises three LNA moieties and at least one 2',5'-linked nucleotide. In some embodiments, the TREM comprises three LNA moieties and one 2',5'-linked nucleotide. In some embodiments, the TREM comprises three LNA moieties and two 2',5'-linked nucleotides. In some embodiments, the TREM comprises three LNA moieties and three 2',5'-linked nucleotides.

[0412] In some embodiments, the TREM comprises four LNA moieties and at least one 2',5'-linked nucleotide. In some embodiments, the TREM comprises four LNA moieties and one 2',5'-linked nucleotide. In some embodiments, the TREM comprises four LNA moieties and two 2',5'-linked nucleotides.

[0413] In some embodiments, the TREM comprising both the LNA moiety and the 2',5'-linked nucleotide also includes at least one additional non-native modification (e.g., a 2'-ribose modification or internucleotide modification, e.g., a 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothiolate modification).

[0414] In some embodiments, the TREM comprising the LNA moiety and the 2',5'-linked nucleotide comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more additional non-natural modifications (e.g., 2'-ribose modifications or internucleotide modifications, e.g., 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothiolate modifications).

[0415] In some embodiments, the TREM comprises one LNA moiety, one 2',5'-linked nucleotide, and at least one 5-methylcytosine.

[0416] In some embodiments, the TREM comprises one LNA moiety, one 2',5'-linked nucleotide, and at least one 2'-moe.

[0417] In one embodiment, the present disclosure is a method for treating a subject having a disease or disorder related to PTC, comprising administering a TREM, TREM core fragment, or TREM fragment (e.g., a TREM as described herein) to the subject, thereby treating the subject having the disease or disorder. In one embodiment, the disease or disorder related to PTC includes hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease.

[0418] In one embodiment, the TREM containing the LNA moiety or 2',5'-linked nucleotides includes a sequence corresponding to the nucleotide sequence of SEQ ID NO: 625. In another embodiment, the TREM containing the LNA moiety or 2',5'-linked nucleotides includes a sequence corresponding to the nucleotide sequence of SEQ ID NO: 1416.

[0419] TREM, TREM core fragments, and TREM fragment fusion In some embodiments, the TREM, TREM core fragment, and TREM fragment disclosed herein include additional parts, such as a fusion portion. In some embodiments, the fusion portion may be used for purification to modify the folding of the TREM, TREM core fragment, and TREM fragment, or it may be used as a targeting portion. In some embodiments, the fusion portion may include a tag, a linker, be cleavable, or include a binding site for an enzyme. In some embodiments, the fusion portion may be located at the N-terminus or C-terminus of the TREM, TREM core fragment, and TREM fragment. In some embodiments, the fusion portion may be encoded by the same or different nucleic acid molecules encoding the TREM, TREM core fragment, and TREM fragment.

[0420] TREM Consensus Array In one embodiment, the TREM disclosed herein includes a consensus sequence provided herein.

[0421] In one embodiment, the TREM disclosed herein is of formula I ZZZ The consensus array ( ZZZ (where represents one of 20 amino acids, and formula I corresponds to all species.)

[0422] In one embodiment, the TREM disclosed herein is Equation II ZZZ The consensus array ( ZZZ Formula II includes one of 20 amino acids (wherein formula II corresponds to mammals).

[0423] In one embodiment, the TREM disclosed herein is Equation III ZZZ The consensus array ( ZZZ (where represents one of 20 amino acids, and formula III corresponds to human).

[0424] In one embodiment, ZZZ This represents one of 20 amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0425] In one embodiment, the TREM disclosed herein is as follows: a) Under physiological conditions, does residue R0 form a linker region, e.g., linker 1 region? b) Under physiological conditions, residues R1-R2-R3-R4-R5-R6-R7 and residues R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 This forms a stem region, for example, an AStD stem region; c) Under physiological conditions, residues R8-R9 form a linker region, e.g., linker 2 region; d) Under physiological conditions, residue-R 10 -R 11 -R 12 -R 13 -R 14 R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 This forms a stem-loop region, for example, a D-arm region; e) Under physiological conditions, residue-R 29 Does this form a linker region, for example, linker 3 region? f) Under physiological conditions, residue R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 This forms a stem-loop region, for example, an AC arm region; g) Under physiological conditions, residue-[R 47 ] x This includes, for example, a variable region as described herein; h) Under physiological conditions, residue-R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R60 -R 61 -R 62 -R 63 -R 64 This forms a stem-loop region, for example, a T-arm region; or i) Under physiological conditions, residue R 72 This forms a linker region, for example, a linker 4 region. Includes characteristics selected from.

[0426] Alanine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I ALA The array (sequence number 562), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51-R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus for Ala is that R0 = non-existent; R 14 , R 57 = Independently A or non-existent; R 26 = A, C, G or non-existent; R5, R6, R 15 , R 16 , R 21 , R 30 , R 31 , R 32 , R 34 , R 37 , R 41 , R 42 , R 43 , R 44 , R 45 , R 48 , R 49 , R 50 , R 58 , R 59 , R 63 , R 64 , R 66 , R 67 = Independently N or non-existent; R 11 , R 35 , R 65 = Independently A, C, U or non-existent; R1, R9, R 20 , R 38 , R 40 , R 51 , R 52 , R 56 = Independently A, G or non-existent; R7, R 22 , R25 , R 27 , R 29 , R 46 , R 53 , R 72 = Independently A, G, U or non-existent; R 24 , R 69 = Independently A, U, or non-existent; R 70 , R 71 = independently C or non-existent; R3, R4 = independently C, G or non-existent; R 12 , R 33 , R 36 , R 62 , R 68 = Independently C, G, U or non-existent; R 13 , R 17 , R 28 , R 39 , R 55 , R 60 , R 61 = Independently C, U, or non-existent; R 10 , R 19 , R 23 = Independently G or non-existent; R2 = G, U or non-existent; R8, R 18 , R 54 = Independently U or non-existent; [R 47 ] x=N or nonexistent; for example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x=1~22, x=1 ~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12, x=1~11, x=1~10, x=10 ~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~271, x=80~271, x=100~271, x=125~27 1, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x= 11, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x= TREM includes (x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) and is subject to the following characteristics: less than 15% of residues are N; or less than 20 residues are absent, or both.

[0427] In one embodiment, the TREM disclosed herein is Equation II ALA The array (sequence number 563) is included, R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ala is, R0, R 18 = non-existent; R 14 , R 24 , R 57 = Independently A or non-existent; R 15 , R 26 , R 64= Independently A, C, G, or non-existent; R 16 , R 31 , R 50 , R 59 = Independently N or non-existent; R 11 , R 32 , R 37 , R 41 , R 43 , R 45 , R 49 , R 65 , R 66 = Independently A, C, U, or non-existent; R1, R5, R9, R 25 , R 27 , R 38 , R 40 , R 46 , R 51 , R 56 = Independently A, G, or non-existent; R7, R 22 , R 29 , R 42 , R 44 , R 53 , R 63 , R 72 = Independently A, G, U, or non-existent; R6, R 35 , R 69 = Independently A, U, or non-existent; R 55 , R 60 , R 70 , R 71 = Independently C or non-existent; R3 = C, G, or non-existent; R 12 , R 36 , R 48 = Independently C, G, U, or non-existent; R 13 , R 17 , R 28 , R 30 , R 34 , R 39 , R 58 , R 61 , R 62 , R 67 , R 68 = Independently C, U, or non-existent; R4, R 10 , R 19 , R 20 , R 23 , R 52 = Independently G or non-existent; R2, R8, R 33 = Independently G, U, or non-existent; R 21 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0428] In one embodiment, the TREM disclosed herein is Equation III ALA Includes the array (sequence number 564), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68-R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Ala is, R0, R 18 = non-existent; R 14 , R 24 , R 57 , R 72 = Independently A or non-existent; R 15 , R 26 , R 64 = Independently A, C, G, or non-existent; R 16 , R 31 , R 50 = Independently N or non-existent; R 11 , R 32 , R 37 , R 41 , R 43 , R 45 , R 49 , R 65 , R 66 = Independently A, C, U, or non-existent; R5, R9, R 25 , R 27 , R 38 , R 40 , R 46 , R 51 , R 56 = Independently A, G, or non-existent; R7, R 22 , R 29 , R 42 , R 44 , R 53 , R 63 = Independently A, G, U, or non-existent; R6, R 35 = Independently A, U, or non-existent; R 55 , R 60 , R 61 , R 70 , R 71 = Independently C or non-existent; R 12 , R 48, R 59 = Independently C, G, U, or non-existent; R 13 , R 17 , R 28 , R 30 , R 34 , R 39 , R 58 , R 62 , R 67 , R 68 = Independently C, U, or non-existent; R1, R2, R3, R4, R 10 , R 19 , R 20 , R 23 , R 52 = Independently G or non-existent; R 33 , R 36 = Independently G, U, or non-existent; R8, R 21 , R 54 , R 69 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0429] Arginine TREM Consensus Sequence In one embodiment, the TREM disclosed herein is of formula I ARG Includes the sequence (sequence number 565), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19-R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Arg is, R 57 = A or non-existent; R9, R 27 = Independently A, C, G, or non-existent; R1, R2, R3, R4, R5, R6, R7, R 11 , R12 , R 16 , R 21 , R 22 , R 23 , R 25 , R 26 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 37 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 51 , R 58 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 = Independently N or non-existent; R 13 , R 17 , R 41 = Independently A, C, U, or non-existent; R 19 , R 20 , R 24 , R 40 , R 56 = Independently A, G, or non-existent; R 14 , R 15 , R 72 = Independently A, G, U, or non-existent; R 18 = A, U, or non-existent; R 38 = C or non-existent; R 35 , R 43 , R 61 = Independently C, G, U, or non-existent; R 28 , R 55 , R 59 , R 60= Independently C, U, or non-existent; R0, R 10 , R 52 = Independently G or non-existent; R8, R 39 = Independently G, U, or non-existent; R 36 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0430] In one embodiment, the TREM disclosed herein is Equation II ARG The array (sequence number 566), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Arg is, R 18 = non-existent; R 24 , R 57 = Independently A or non-existent; R 41 = A, C, or non-existent; R3, R7, R 34 , R 50 = Independently A, C, G, or non-existent; R2, R5, R6, R 12 , R 26 , R 32 , R 37 , R 44 , R 58 , R 66 , R 67 , R 68 , R 70 = Independently N or non-existent; R 49 , R 71 = Independently A, C, U, or non-existent; R1, R 15 , R 19 , R 25 , R 27 , R 40 , R 45 , R 46 , R 56 , R 72 = Independently A, G, or non-existent; R 14 , R 29 , R 63 = Independently A, G, U, or non-existent; R 16 , R 21 = Independently A, U, or non-existent; R 38 , R 61 = Independently C or non-existent; R 33 , R 48 = Independently C, G, or non-existent; R4, R9, R 11, R 43 , R 62 , R 64 , R 69 = Independently C, G, U, or non-existent; R 13 , R 22 , R 28 , R 30 , R 31 , R 35 , R 55 , R 60 , R 65 = Independently C, U, or non-existent; R0, R 10 , R 20 , R 23 , R 51 , R 52 = Independently G or non-existent; R8, R 39 , R 42 = Independently G, U, or non-existent; R 17 , R 36 , R 53 , R 54 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0431] In one embodiment, the TREM disclosed herein is Equation III ARG The array (sequence number 567), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Arg is, R 18 = non-existent; R 15 , R 21 , R 24 , R 41 , R 57 = Independently A or non-existent; R 34 , R44 = Independently A, C, or non-existent; R3, R5, R 58 = Independently A, C, G, or non-existent; R2, R6, R 66 , R 70 = Independently N or non-existent; R 37 , R 49 = Independently A, C, U, or non-existent; R1, R 25 , R 29 , R 40 , R 45 , R 46 , R 50 = Independently A, G, or non-existent; R 14 , R 63 , R 68 = Independently A, G, U, or non-existent; R 16 = A, U, or non-existent; R 38 , R 61 = Independently C or non-existent; R7, R 11 , R 12 , R 26 , R 48 = Independently C, G, or non-existent; R 64 , R 67 , R 69 = Independently C, G, U, or non-existent; R4, R 13 , R 22 , R 28 , R 30 , R 31 , R 35 , R 43 , R 55 , R 60 , R 62 , R 65 , R 71 = Independently C, U, or non-existent; R0, R 10 , R 19 , R 20 , R 23 , R 27 , R 33 , R 51 , R52 , R 56 , R 72 = Independently G or non-existent; R8, R9, R 32 , R 39 , R 42 = Independently G, U, or non-existent; R 17 , R 36 , R 53 , R 54 , R 59 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0432] Asparagine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I ASN The array (sequence number 568), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asn is, R0, R 18 = non-existent; R 41 = A or non-existent; R 14 , R 48 , R 56 = Independently A, C, G, or non-existent; R2, R4, R5, R6, R 12 , R 17 , R 26 , R 29 , R 30 , R 31 , R 44 , R 45 , R 46 , R 49 , R 50 , R 58 , R 62 , R 63 , R 65 , R 66 , R 67 , R 68 , R 70 , R 71 = Independently N or non-existent; R 11 , R 13 , R 22 , R 42 , R 55 , R 59 = Independently A, C, U, or non-existent; R9, R 15 , R 24 , R 27 , R 34 , R 37 , R 51 , R 72 = Independently A, G, or non-existent; R1, R7, R 25 , R 69 = Independently A, G, U, or non-existent; R40 , R 57 = Independently A, U, or non-existent; R 60 = C or non-existent; R 33 = C, G, or non-existent; R 21 , R 32 , R 43 , R 64 = Independently C, G, U, or non-existent; R3, R 16 , R 28 , R 35 , R 36 , R 61 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 52 = Independently G or non-existent; R 54 = G, U, or non-existent; R8, R 23 , R 38 , R 39 , R 53 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0433] In one embodiment, the TREM disclosed herein is Equation II ASN Includes the sequence (sequence number 569), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asn is, R0, R 18 = non-existent, R 24 , R 41 , R 46 , R 62 = Independently A or non-existent; R 59 = A, C, or non-existent; R 14 , R 56 , R 66 = Independently A, C, G, or non-existent; R 17 , R 29 = Independently N or non-existent; R 11 , R 26 , R 42 , R 55 = Independently A, C, U, or non-existent; R1, R9, R 12 , R 15 , R 25 , R 34 , R 37 , R 48 , R 51 , R 67 , R 68 , R 69 , R 70 , R 72 = Independently A, G, or non-existent; R 44 , R 45 , R 58 = Independently A, G, U, or non-existent; R 40 , R 57 = Independently A, U, or non-existent; R5, R 28 , R 60 = Independently C or non-existent; R 33 , R 65 = Independently C, G, or non-existent; R 21 , R 43 , R 71 = Independently C, G, U, or non-existent; R3, R6, R 13 , R 22 , R 32 , R 35 , R 36 , R 61 , R 63 , R 64 = Independently C, U, or non-existent; R7, R 10 , R 19 , R 20 , R 27 , R49 , R 52 = Independently G or non-existent; R 54 = G, U, or non-existent; R2, R4, R8, R 16 , R 23 , R 30 , R 31 , R 38 , R 39 , R 50 , R 53 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0434] In one embodiment, the TREM disclosed herein is Equation III ASN Includes the sequence (sequence number 570), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asn is, R0, R 18 = non-existent, R 24 , R 40 , R 41 , R 46 , R 62 = Independently A or non-existent; R 59 = A, C, or non-existent; R 14 , R 56 , R 66 = Independently A, C, G, or non-existent; R 11 , R 26 , R 42 , R 55 = Independently A, C, U, or non-existent; R1, R9, R 12 , R 15 , R 34 , R 37 , R 48 , R 51 , R 67 , R 68 , R 69 , R 70 = Independently A, G, or non-existent; R 44 , R 45 , R 58 = Independently A, G, U, or non-existent; R 57 = A, U, or non-existent; R5, R 28 , R 60 = Independently C or non-existent; R 33 , R 65 = Independently C, G, or non-existent; R 17 , R 21 , R 29 = Independently C, G, U, or non-existent; R3, R6, R13 , R 22 , R 32 , R 35 , R 36 , R 43 , R 61 , R 63 , R 64 , R 71 = Independently C, U, or non-existent; R7, R 10 , R 19 , R 20 , R 25 , R 27 , R 49 , R 52 , R 72 = Independently G or non-existent; R 54 = G, U, or non-existent; R2, R4, R8, R 16 , R 23 , R 30 , R 31 , R 38 , R 39 , R 50 , R 53 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0435] Aspartate TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I ASP Includes the sequence (sequence number 571), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19-R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asp is, R0 = non-existence, R 24 , R 71 = Independently A, C, or non-existent; R 33 , R 46= Independently A, C, G, or non-existent; R2, R3, R4, R5, R6, R 12 , R 16 , R 22 , R 26 , R 29 , R 31 , R 32 , R 44 , R 48 , R 49 , R 58 , R 63 , R 64 , R 66 , R 67 , R 68 , R 69 = Independently N or non-existent; R 13 , R 21 , R 34 , R 41 , R 57 , R 65 = Independently A, C, U, or non-existent; R9, R 10 , R 14 , R 15 , R 20 , R 27 , R 37 , R 40 , R 51 , R 56 , R 72 = Independently A, G, or non-existent; R7, R 25 , R 42 = Independently A, G, U, or non-existent; R 39 = C or non-existent; R 50 , R 62 = Independently C, G, or non-existent; R 30 , R 43 , R 45 , R 55 , R 70 = Independently C, G, U, or non-existent; R8, R 11 , R 17 , R 18 , R 28 , R 35 , R 53 , R59 , R 60 , R 61 = Independently C, U, or non-existent; R 19 , R 52 = Independently G or non-existent; R1 = G, U, or non-existent; R 23 , R 36 , R 38 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0436] In one embodiment, the TREM disclosed herein is Equation II ASP Includes the sequence (sequence number 572), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asp is, R0, R 17 , R 18 , R 23 = Independently non-existent; R9, R 40 = Independently A or non-existent; R 24 , R 71 = Independently A, C, or non-existent; R 67 , R 68 = Independently A, C, G, or non-existent; R2, R6, R 66 = Independently N or non-existent; R 57 , R 63 = Independently A, C, U, or non-existent; R 10 , R 14 , R 27 , R 33 , R 37 , R 44 , R 46 , R 51 , R 56 , R 64 , R 72 = Independently A, G, or non-existent; R7, R 12 , R 26 , R 65 = Independently A, U, or non-existent; R 39 , R 61 , R 62 = Independently C or non-existent; R3, R 31 , R 45 , R 70 = Independently C, G, or non-existent; R4, R5, R 29 , R 43 , R 55 = Independently C, G, U, or non-existent; R8, R11 , R 13 , R 30 , R 32 , R 34 , R 35 , R 41 , R 48 , R 53 , R 59 , R 60 = Independently C, U, or non-existent; R 15 , R 19 , R 20 , R 25 , R 42 , R 50 , R 52 = Independently G or non-existent; R1, R 22 , R 49 , R 58 , R 69 = Independently G, U, or non-existent; R 16 , R 21 , R 28 , R 36 , R 38 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0437] In one embodiment, the TREM disclosed herein is Equation III ASP Includes the sequence (sequence number 573), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Asp is, R0, R 17 , R 18 , R 23 = non-existent, R9, R 12 , R 40 , R 65 , R 71 = Independently A or non-existent; R2, R 24 , R 57 = Independently A, C, or non-existent; R6, R 14 , R 27 , R 46 , R 51 , R 56 , R 64 , R 67 , R 68 = Independently A, G, or non-existent; R3, R 31 , R 35 , R 39 , R 61 , R 62 = Independently C or non-existent; R 66 = C, G, or non-existent; R5, R8, R 29 , R 30 , R 32 , R 34 , R 41 , R 43 , R 48 , R 55 , R 59 , R 60 , R 63 = Independently C, U, or non-existent; R 10 , R 15 , R 19 , R 20 , R 25 , R 33 , R 37 , R 42 , R 44 , R 45 , R 49 , R 50 , R 52 , R 69 , R 70 , R 72 = Independently G or non-existent; R 22 , R 58 = Independently G, U, or non-existent; R1, R4, R7, R 11 , R 13 , R 16 , R 21 , R 26 , R 28 , R 36 , R38 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0438] Cysteine ​​TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I CYS Includes the array (sequence number 574), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11-R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Cys is, R0 = non-existence, R 14 , R 39 , R 57 = Independently A or non-existent; R 41 = A, C, or non-existent; R 10 , R 15 , R 27 , R 33 , R 62 = Independently A, C, G, or non-existent; R3, R4, R5, R6, R 12 , R 13 , R 16 , R 24 , R 26 , R 29 , R 30 , R 31 , R 32 , R 34 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 58 , R 63 , R 64 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 65 = A, C, U, or non-existent; R9, R 25 , R 37 , R 40 , R 52 , R 56 = Independently A, G, or non-existent; R7, R 20 , R 51 = Independently A, G, U, or non-existent; R 18 , R 38 , R 55 = Independently C or non-existent; R2 = C, G, or non-existent; R 21 , R 28 , R 43 , R50 = Independently C, G, U, or non-existent; R 11 , R 22 , R 23 , R 35 , R 36 , R 59 , R 60 , R 61 , R 71 , R 72 = Independently C, U, or non-existent; R1, R 19 = Independently G or non-existent; R 17 = G, U, or non-existent; R8, R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0439] In one embodiment, the TREM disclosed herein is Equation II CYS Includes the sequence (sequence number 575), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Cys is, R0, R 18 , R 23 = non-existent; R 14 , R 24 , R 26 , R 29 , R 39 , R 41 , R 45 , R57 = Independently A or non-existent; R 44 = A, C, or non-existent; R 27 , R 62 = Independently A, C, G, or non-existent; R 16 = A, C, G, U, or non-existent; R 30 , R 70 = Independently A, C, U, or non-existent; R5, R7, R9, R 25 , R 34 , R 37 , R 40 , R 46 , R 52 , R 56 , R 58 , R 66 = Independently A, G, or non-existent; R 20 , R 51 = Independently A, G, U, or non-existent; R 35 , R 38 , R 43 , R 55 , R 69 = Independently C or non-existent; R2, R4, R 15 = Independently C, G, or non-existent; R 13 = C, G, U, or non-existent; R6, R 11 , R 28 , R 36 , R 48 , R 49 , R 50 , R 60 , R 61 , R 67 , R 68 , R 71 , R 72 = Independently C, U, or non-existent; R1, R3, R 10 , R 19 , R 33 , R 63 = Independently G or non-existent; R8, R 17 , R21 , R 64 = Independently G, U, or non-existent; R 12 , R 22 , R 31 , R 32 , R 42 , R 53 , R 54 , R 65 = Independently U or non-existent; R 59 =U, or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0440] In one embodiment, the TREM disclosed herein is Equation III CYS Includes the sequence (sequence number 576), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Cys is, R0, R 18 , R 23 = non-existent, R 14 , R 24 , R 26 , R 29 , R 34 , R 39 , R 41 , R 45 , R 57 , R 58 = Independently A or non-existent; R 44 , R 70 = Independently A, C, or non-existent; R 62 = A, C, G or non-existent; R 16 =N or nonexistent; R5, R7, R9, R 20 , R 40 , R 46 , R 51 , R 52 , R 56 , R 66 = Independently A, G, or non-existent; R 28 , R 35 , R 38 , R 43 , R 55 , R 67 , R 69 = Independently C or non-existent; R4, R 15 = Independently C, G, or non-existent; R6, R 11 , R 13 , R 30 , R 48 , R 49 , R 50 , R 60 , R 61 , R 68 , R 71 , R72 = Independently C, U, or non-existent; R1, R2, R3, R 10 , R 19 , R 25 , R 27 , R 33 , R 37 , R 63 = Independently G or non-existent; R8, R 21 , R 64 = Independently G, U, or non-existent; R 12 , R 17 , R 22 , R 31 , R 32 , R 36 , R 42 , R 53 , R 54 , R 59 , R 65 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0441] Glutamine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I GLN Includes the sequence (sequence number 577), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19-R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Gln is, R0, R 18 = non-existent; R 14 , R 24 , R 57 = Independently A or non-existent; R9, R 26 , R27 , R 33 , R 56 = Independently A, C, G, or non-existent; R2, R4, R5, R6, R 12 , R 13 , R 16 , R 21 , R 22 , R 25 , R 29 , R 30 , R 31 , R 32 , R 34 , R 41 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 17 , R 23 , R 43 , R 65 , R 71 = Independently A, C, U, or non-existent; R 15 , R 40 , R 51 , R 52 = Independently A, G, or non-existent; R1, R7, R 72 = Independently A, G, U, or non-existent; R3, R 11 , R 37 , R 60 , R 64 = Independently C, G, U, or non-existent; R 28 , R 35 , R 55 , R 59 , R 61 = Independently C, U, or non-existent; R 10 , R 19 , R20 = Independently G or non-existent; R 39 = G, U, or non-existent; R8, R 36 , R 38 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0442] In one embodiment, the TREM disclosed herein is Equation II GLN The array (sequence number 578), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Gln is, R0, R 18 , R 23 = non-existent, R 14 , R 24 , R 57 = Independently A or non-existent; R 17 , R 71 = Independently A, C, or non-existent; R 25 , R 26 , R 33 , R 44 , R 46 , R 56 , R 69 = Independently A, C, G, or non-existent; R4, R5, R 12 , R 22 , R 29 , R 30 , R 48 , R 49 , R 63 , R 67 , R 68 = Independently N or non-existent; R 31 , R 43 , R 62 , R 65 , R 70 = Independently A, C, U, or non-existent; R 15 , R 27 , R 34 , R 40 , R 41 , R 51 , R 52 = Independently A, G, or non-existent; R2, R7, R 21 , R 45 , R 50 , R 58 , R 66 , R 72 = Independently A, G, U, or non-existent; R3, R 13 , R 32 , R 37 , R 42 , R 60 , R64 = Independently C, G, U, or non-existent; R6, R 11 , R 28 , R 35 , R 55 , R 59 , R 61 = Independently C, U, or non-existent; R9, R 10 , R 19 , R 20 = Independently G or non-existent; R1, R 16 , R 39 = Independently G, U, or non-existent; R8, R 36 , R 38 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0443] In one embodiment, the TREM disclosed herein is Equation III GLN The array (sequence number 579), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21-R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Gln is, R0, R 18 , R 23 = non-existent, R 14 , R 24 , R 41 , R 57 = Independently A or non-existent; R 17 , R71 = Independently A, C, or non-existent; R5, R 25 , R 26 , R 46 , R 56 , R 69 = Independently A, C, G, or non-existent; R4, R 22 , R 29 , R 30 , R 48 , R 49 , R 63 , R 68 = Independently N or non-existent; R 43 , R 62 , R 65 , R 70 = Independently A, C, U, or non-existent; R 15 , R 27 , R 33 , R 34 , R 40 , R 51 , R 52 = Independently A, G, or non-existent; R2, R7, R 12 , R 45 , R 50 , R 58 , R 66 = Independently A, G, U, or non-existent; R 31 = A, U, or non-existent; R 32 , R 44 , R 60 = Independently C, G, or non-existent; R3, R 13 , R 37 , R 42 , R 64 , R 67 = Independently C, G, U, or non-existent; R6, R 11 , R 28 , R 35 , R 55 , R 59 , R 61 = Independently C, U, or non-existent; R9, R 10 , R 19 , R20 = Independently G or non-existent; R1, R 21 , R 39 , R 72 = Independently G, U, or non-existent; R8, R 16 , R 36 , R 38 , R 53 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0444] Glutamate TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I GLU The array (sequence number 580), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Glu is, R0 = non-existence; R 34 , R 43 , R 68 , R 69 = Independently A, C, G, or non-existent; R1, R2, R5, R6, R9, R 12 , R 16 , R 20 , R 21 , R 26 , R 27 , R 29 , R 30 , R 31 , R 32 , R 33 , R 41 , R 44 , R 45 , R 46 , R 48 , R 50 , R 51 , R 58 , R 63 , R 64 , R 65 , R 66 , R 70 , R 71 = Independently N or non-existent; R 13 , R 17 , R 23 , R 61 = Independently A, C, U, or non-existent; R 10 , R 14 , R 24 , R 40 , R 52 , R 56 = Independently A, G, or non-existent; R7, R 15 , R 25 , R 67 , R 72 = Independently A, G, U, or non-existent; R 11 , R57 = Independently A, U, or non-existent; R 39 = C, G, or non-existent; R3, R4, R 22 , R 42 , R 49 , R 55 , R 62 = Independently C, G, U, or non-existent; R 18 , R 28 , R 35 , R 37 , R 53 , R 59 , R 60 = Independently C, U, or non-existent; R 19 =G or non-existent; R8, R 36 , R 38 , R 54 = Independently U or non-existent; [R 47 ] x =N or nonexistent; For example, x=1~271 (for example, x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x=1 ~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 (8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) TREM is provided that it contains the following characteristics: 15% or less of the residues are N; or 20 or less of the residues are absent, or both.

[0445] In one embodiment, the TREM disclosed herein is Equation II GLU The array (sequence number 581), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Glu is, R0, R 18 , R 23 = non-existent, R 17 , R 40 = Independently A or non-existent; R 26 , R 27 , R 34 , R43 , R 68 , R 69 , R 71 = Independently A, C, G, or non-existent; R1, R2, R5, R 12 , R 21 , R 31 , R 33 , R 41 , R 45 , R 48 , R 51 , R 58 , R 66 , R 70 = Independently N or non-existent; R 44 , R 61 = Independent...

Claims

1. The arrangement of equation (A): [L1]x - [AST Domain 1] - [L2]x - [DH Domain] - [L3]x - [ACH Domain] - [VL Domain] - [TH Domain] - [L4]x - [AST Domain 2] - [L5]x (A) A tRNA effector molecule (TREM) containing, in the formula: Independently, [L1], [L5], and [VL domain] are optional; x is 0 or 1; A tRNA effector molecule (TREM) in which the nucleotides within the TREM sequence include a lock nucleic acid (LNA) moiety or a 2',5'-linked nucleotide.

2. The TREM according to claim 1, wherein the LNA portion comprises a heterocyclyl ring or cycloalkyl ring between the 2' and 4' positions of the nucleotide sugar within the nucleotide.

3. The nucleotides in the TREM sequence including the LNA portion are defined by formula (II): 【Chemistry 108】 Or having the structure of its salt, stereoisomer, tautomer, or hydrate, in the formula: B is a nucleic acid base; Y is C(R'), O, or N(R Ｂ ) and; R １ 、 R ２ 、 and R ３ each of which is independently hydrogen, C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C １ ~C ６ heteroalkyl, C １ ~C ６ haloalkyl, halo, cyano, -OR Ａ 、 or -N(R Ｂ )(R Ｃ ), where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R １０ ; L and X, independently, C １ ~C ６ Alkylene, C ２ ~C ６ Alkenylene, C ２ ~C ６ Alkinylene, C １ ~C ６ Heteroalkylene C １ ~C ６ Haloalkylene-O-,-N(R) Ｂ )-,-S(R Ｄ ) ｘ -, -Se(R Ｅ ) ｙ - and here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R １１ Replaced by optional selection; M and Z are both non-existent, C １ ~C ６ Alkylene, C ２ ~C ６ Alkenylene, C ２ ~C ６ Alkinylene, C １ ~C ６ Heteroalkylene C １ ~C ６ Haloalkylene-O-,-N(R) Ｂ )-, S(R Ｄ ) ｘ , -Se(R Ｅ ) ｙ Here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R １１ Replaced by optional selection; R ４ａ and R ４ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R' is hydrogen or C １ ~C ６ It is alkyl; Each R Ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ It is a haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Ｂ and R Ｃ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ It is a heteroalkyl, cycloalkyl, or heterocyclyl; or R Ｂ and R Ｃ However, together with the atoms to which they are bonded, one or more R １１ It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R Ｄ and R Ｅ are, independently, C １ to C ６ alkyl or oxo; R １０ and R １１ each of which is, independently, C １ to C ６ alkyl, C １ to C ６ heteroalkyl, C １ to C ６ haloalkyl, halo, cyano, or -OR Ａ１ ; R Ａ１ However, hydrogen or C １ ~C ６ It is alkyl; x and y are independently 0, 1, or 2; 【Chemistry 109】 However, this refers to the remaining portion of the TREM sequence, another atom, or a bond point to the end of the TREM; However, two or fewer of L, M, Z, and Z are -O-, -N(R Ｂ )-, S(R Ｄ ) ｘ , -Se(R Ｅ ) ｙ It is possible that one of L, M, Z, and Z is O-, -N(R Ｂ )-, S(R Ｄ ) ｘ , -Se(R Ｅ ) ｙ If so, each direct covalent partner selected from L, M, Z, and X is also O-, -N(R Ｂ )-, S(R Ｄ ) ｘ , -Se(R Ｅ ) ｙ The TREM according to claim 1 or 2, not the TREM described in claim 1 or 2.

4. The TREM according to claim 3, wherein B is a natural nucleic acid base (e.g., adenine, cytosine, guanine, uracil).

5. The TREM according to any one of claims 1 to 4, wherein the TREM further comprises chemical modification (e.g., natural chemical modification or non-natural chemical modification).

6. The TREM according to claim 5, wherein the chemical modification is a nucleotide sugar modification, a nucleic acid base modification, or an internucleotide bond modification.

7. The TREM according to claim 5 or 6, wherein the chemical modification includes a 2'OMe modification, a 2'halo (e.g., 2'F or 2'Cl) modification, a 2'MOE modification, a 2'-deoxy modification, or a phosphorothioate modification.

8. The TREM according to any one of claims 5 to 7, wherein the TREM does not contain chemical modifications (e.g., natural chemical modifications or non-natural chemical modifications).

9. A TREM according to any one of claims 1 to 8, wherein the TREM includes a single LNA portion.

10. The TREM according to any one of claims 1 to 9, wherein the TREM includes a plurality of LNA portions.

11. The TREM according to any one of claims 1 to 10, wherein the TREM includes at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 LNA portions.

12. The TREM according to any one of claims 1 to 11, wherein the LNA portion is located in the [L1]-[AST domain 1]-[L2].

13. The TREM according to any one of claims 1 to 12, wherein the LNA portion is located in the [L1]-[AST domain 1]-[L2].

14. The TREM according to any one of claims 1 to 13, wherein the LNA portion is located in the [L2]-[DH domain]-[L3].

15. The TREM according to any one of claims 1 to 14, wherein the LNA portion is located in the [L3]-[ACH domain].

16. The TREM according to any one of claims 1 to 15, wherein the LNA portion is located within the [VL domain].

17. The TREM according to any one of claims 1 to 16, wherein the LNA portion is located in the [TH domain].

18. The TREM according to any one of claims 1 to 17, wherein the LNA portion is located in the [L4]-[AST domain 2]-[L5].

19. The TREM according to any one of claims 1 to 18, wherein the TREM has a sequence selected from the sequences provided in Figure 1.

20. The TREM according to any one of claims 1 to 19, wherein the TREM includes a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with the TREM provided in Figure 1.

21. The TREM according to any one of claims 1 to 20, wherein the TREM comprises a sequence that differs from the TREM provided in Figure 1 by only 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer nucleotides.

22. The TREM according to any one of claims 1 to 21, wherein the TREM comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-natural modifications compared to the TREM provided in Figure 1 (e.g., 2'-ribose modification or internucleotide modification, e.g., 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, LNA, or phosphorothiolate modification).

23. The TREM according to any one of claims 1 to 22, wherein the TREM comprises one nucleotide sequence from sequence numbers 625 to 1416.

24. The nucleotides in the TREM sequence including the LNA portion are of formula (II-e): 【Chemical 110】 Or having the structure of its salt, stereoisomer, tautomer, or hydrate, in the formula: B is a nucleic acid base; Y is C(R'), O, or N(R Ｂ ) and; R １ , R ２ , and R ３ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; X is C １ ~C ６ Alkylene, C ２ ~C ６ Alkenylene, C ２ ~C ６ Alkinylene, C １ ~C ６ Heteroalkylene C １ ~C ６ Haloalkylene-O-,-N(R) Ｂ )-,-S(R Ｄ ) ｘ -, -Se(R Ｅ ) ｙ - and here, each alkylene, alkenylene, alkynylene, heteroalkylene, and haloalkylene is one or more R １１ Replaced by optional selection; R ４ａ and R ４ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ５ａ and R ５ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R' is hydrogen or C １ ~C ６ It is alkyl; Each R Ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ It is a haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Ｂ and R Ｃ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ It is a heteroalkyl, cycloalkyl, or heterocyclyl; or R Ｂ and R Ｃ However, together with the atoms to which they are bonded, one or more R １１ It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R Ｄ and R Ｅ However, independently, C １ ~C ６ Alkyl or oxo; R １０ and R １１ Each of these independently, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, or -OR Ａ１ And; R Ａ１ However, hydrogen or C １ ~C ６ It is alkyl; x and y are independently 0, 1, or 2; n is 1, 2, 3, 4, 5, or 6; 【Chemistry 111】 The TREM according to any one of claims 1 to 23, wherein the TREM refers to the remaining portion of the TREM sequence, another atom, or a bond point to the end of the TREM.

25. The nucleotide in the TREM sequence including the LNA portion is defined by formula (II-m): 【Chemistry 112】 Or having the structure of its salt, stereoisomer, tautomer, or hydrate, in the formula: B is a nucleic acid base; R １ , R ２ , and R ３ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ４ａ and R ４ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ５ａ and R ５ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ６ａ and R ６ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R' is hydrogen or C １ ~C ６ It is alkyl; Each R Ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ It is a haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Ｂ and R Ｃ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ It is a heteroalkyl, cycloalkyl, or heterocyclyl; or R Ｂ and R Ｃ However, together with the atoms to which they are bonded, one or more R １１ It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R Ｄ and R Ｅ However, independently, C １ ~C ６ Alkyl or oxo; R １０ and R １１ Each of these independently, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, or -OR Ａ１ And; R Ａ１ However, hydrogen or C １ ~C ６ It is alkyl; x and y are independently 0, 1, or 2; 【Chemistry 113】 The TREM according to any one of claims 1 to 24, wherein the TREM refers to the remaining portion of the TREM sequence, another atom, or a bond point to the end of the TREM.

26. The nucleotides in the TREM sequence containing the 2',5'-linked nucleotides are defined by formula (III): 【Chemical 114】 Or having the structure of its salt, stereoisomer, tautomer, or hydrate, in the formula: B is a nucleic acid base; Y is C(R'), O, or N(R Ｂ ) and; R １ , R ２ , and R ４ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ３ａ and R ３ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ５ａ and R ５ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R' is hydrogen or C １ ~C ６ It is alkyl; Each R Ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ It is a haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Ｂ and R Ｃ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ It is a heteroalkyl, cycloalkyl, or heterocyclyl; or R Ｂ and R Ｃ However, together with the atoms to which they are bonded, one or more R １１ It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; R １０ However, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, or -OR Ａ１ And; R Ａ１ However, hydrogen or C １ ~C ６ It is alkyl; x and y are independently 0, 1, or 2; 【Chemical 115】 The TREM according to any one of claims 1 to 25, wherein the TREM refers to the remaining portion of the TREM sequence, another atom, or a bond point to the end of the TREM.

27. The TREM according to claim 26, wherein B is a natural nucleic acid base (e.g., adenine, cytosine, guanine, uracil).

28. The TREM according to claim 26 or 27, wherein the TREM further comprises chemical modification (e.g., natural chemical modification or non-natural chemical modification).

29. The TREM according to any one of claims 26 to 28, wherein the chemical modification is a nucleotide sugar modification, a nucleic acid base modification, or an internucleotide bond modification.

30. The TREM according to claim 28 or 29, wherein the chemical modification includes a 2'OMe modification, a 2'halo (e.g., 2'F or 2'Cl) modification, a 2'MOE modification, a 2'-deoxy modification, or a phosphorothioate modification.

31. The TREM according to any one of claims 26 to 30, wherein the compound of formula (III) is free from chemical modifications (e.g., natural or non-natural chemical modifications).

32. The TREM according to any one of claims 26 to 31, wherein the TREM comprises a single 2',5'-linked nucleotide moiety.

33. The TREM according to any one of claims 26 to 32, wherein the TREM comprises a plurality of 2',5'-linked nucleotide moieties.

34. The TREM according to any one of claims 26 to 33, wherein the TREM comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 2',5'-linked nucleotides.

35. The TREM according to any one of claims 26 to 34, wherein the 2',5'-linked nucleotide is present in the [L1]-[ASt domain 1]-[L2].

36. The TREM according to any one of claims 26 to 35, wherein the 2',5'-linked nucleotide is present in the [L1]-[ASt domain 1]-[L2].

37. The TREM according to any one of claims 26 to 36, wherein the 2',5'-linked nucleotide is present in the [L2]-[DH domain]-[L3].

38. The TREM according to any one of claims 26 to 37, wherein the 2',5'-linked nucleotide is present in the [L3]-[ACH domain].

39. The TREM according to any one of claims 26 to 38, wherein the 2',5'-linked nucleotide is present in the [VL domain].

40. The TREM according to any one of claims 26 to 39, wherein the 2',5'-linked nucleotide is present in the [TH domain].

41. The TREM according to any one of claims 26 to 40, wherein the 2',5'-linked nucleotide is present in the [L4]-[ASt domain 2]-[L5].

42. The TREM according to any one of claims 26 to 41, wherein the TREM has a sequence selected from the sequences provided in Figure 1.

43. The TREM according to any one of claims 26 to 42, wherein the TREM includes a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with the TREM provided in Figure 1.

44. The TREM according to any one of claims 26 to 43, wherein the TREM comprises a sequence that differs from the TREM provided in Figure 1 by only 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or fewer nucleotides.

45. The TREM according to any one of claims 26 to 44, wherein the TREM comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-natural modifications compared to the TREM provided in Figure 1 (e.g., 2'-ribose modification or internucleotide modification, e.g., 2'OMe, 2'-halo, 2'-MOE, 2'-deoxy, or phosphorothiolate modification).

46. The nucleotide in the TREM sequence containing the 2',5'-linked nucleotide is defined by formula (III-a): 【Chemistry 116】 Or having the structure of its salt, stereoisomer, tautomer, or hydrate, in the formula: B is a nucleic acid base; Y is C(R'), O, or N(R Ｂ ) and; R １ , R ２ , and R ４ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ３ａ However, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ３ｃ However, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, or C １ ~C ６ It is a haloalkyl, where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R ５ａ and R ５ｂ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, -OR Ａ , or -N(R Ｂ ) (Caution Ｃ ) where each alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl is one or more R １０ Replaced by optional selection; R' is hydrogen or C １ ~C ６ It is alkyl; Each R Ａ However, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ It is a haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Ｂ and R Ｃ Each of them independently produces hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ It is a heteroalkyl, cycloalkyl, or heterocyclyl; or R Ｂ and R Ｃ However, together with the atoms to which they are bonded, one or more R １１ It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; R １０ However, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, cyano, or -OR Ａ１ And; R Ａ１ However, hydrogen or C １ ~C ６ It is alkyl; x and y are independently 0, 1, or 2; 【Chemistry 117】 The TREM according to any one of claims 26 to 46, wherein the TREM refers to the remaining portion of the TREM sequence, another atom, or a bond point to the end of the TREM.

47. The TREM according to any one of claims 1 to 46, wherein the TREM comprises one nucleotide sequence from sequence numbers 625 to 793.

48. The TREM according to any one of claims 1 to 47, wherein the TREM comprises one nucleotide sequence from sequence numbers 793 to 1416.

49. The TREM according to any one of claims 26 to 45, wherein the TREM comprises a nucleotide sequence selected from any one of sequence numbers 625 to 1416.

50. A pharmaceutical composition comprising TREM as described in any one of claims 1 to 49.

51. The pharmaceutical composition according to claim 50, further comprising pharmaceutically acceptable components, for example, excipients.

52. A lipid nanoparticle formulation comprising TREM according to any one of claims 1 to 49.

53. A lipid nanoparticle formulation comprising the pharmaceutical composition according to claim 50 or 51.

54. A composition for use in the treatment of a subject having a disease or disorder related to PTC, comprising administering a TREM as described herein (for example, a TREM as described in any one of claims 1 to 49) to the subject.

55. The composition for use according to claim 54, wherein the disease or disorder related to PTC includes hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease.

56. A method for treating a subject having a disease or disorder related to PTC, comprising administering a TREM described herein (for example, a TREM described in any one of claims 1 to 49) to the subject, thereby treating the subject having the disease or disorder.

57. The method according to claim 56, wherein the disease or disorder related to PTC includes hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease.

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