TREM composition and its use

Abstract

To provide tRNA-based effector molecules having unnatural modifications and related methods. [Solution] 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, at least one modification (e.g., a non-native modification) on a component nucleotide (e.g., a nucleic acid base or sugar) or in an internucleotide region, e.g., within the TREM backbone.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 009,669, filed on 14 April 2020, the entire contents of which are incorporated herein by reference. [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. The TREMs disclosed herein include, for example, at least one modification (e.g., a non-native modification) on a component nucleotide (e.g., a nucleic acid base or sugar) or in an internucleotide region, e.g., within the TREM backbone. In one embodiment, the TREM is provided herein, comprising the sequence of formula A: [L1]-[ASt domain 1]-[L2]-[DH domain]-[L3]-[ACH domain]-[VL domain]-[TH domain]-[L4]-[ASt domain 2], wherein [L1] and [VL domain] are independently optional; 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 with an unnatural modification.

[0004] In one embodiment, TREM has the ability to: (a) (i) assist in protein synthesis, (ii) be modified by synthetases, (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 greater than 3, 4, 5, 6, 7, 8, 9, or 10; (c) comprise at least three but less than all of a nucleotide of type (e.g., A, T, C, G, or U) that have the same unnatural modifications; and (d) comprise at least X of type (e.g., A, T, C, G, or U) that do not have unnatural modifications. (e) comprising nucleotides, where X = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; (e) comprising 5, 10, or 15 or fewer nucleotides of a type containing unnatural modifications (e.g., A, T, C, G, or U); and / or (f) comprising 5, 10, or 15 or fewer nucleotides of a type not containing unnatural modifications (e.g., A, T, C, G, or U).

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

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

[0007] In certain aspects, herein, 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 is provided, wherein the TREM core fragment: 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.

[0008] In certain embodiments, TREM has the ability to assist protein synthesis. In certain embodiments, TREM has the ability to be altered by synthetase. In certain embodiments, TREM has the ability to be bound by an elongation factor. In certain embodiments, TREM has the ability to introduce an amino acid into a peptide chain. In certain embodiments, TREM has the ability to assist elongation. In certain embodiments, TREM has the ability to assist initiation.

[0009] In certain embodiments, [ASt domain 1] and / or [ASt domain 2] comprising a non-natural modification has the ability to initiate or elongate a polypeptide chain.

[0010] In certain embodiments, [ACH domain] comprising a non-natural modification has the ability to mediate codon pairing.

[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: 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 modification of the nucleotide base or backbone, for example, a modification selected from any one of Tables 5, 6, 7, 8, or 9.

[0029] 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.

[0030] 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 6.

[0031] 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 7.

[0032] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the non-natural modification is a skeletal modification selected from the modifications listed in Table 8.

[0033] In some embodiments of the TREM, TREM core fragment, or TREM fragment disclosed herein, the non-natural modification is a skeletal modification selected from the modifications listed in Table 9.

[0034] 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.

[0035] 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.

[0036] 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 any one of Tables 15 to 22, for example, any one of Sequence IDs 622 to 1187. In some embodiments, the TREM, TREM core fragment, or TREM fragment is coded by a sequence provided in Table 15, for example, any one of Sequence IDs 622 to 698. In some embodiments, the TREM, TREM core fragment, or TREM fragment is coded by a sequence provided in Table 16, for example, any one of Sequence IDs 699 to 774. In some embodiments, the TREM, TREM core fragment, or TREM fragment is coded by a sequence provided in Table 17, for example, any one of Sequence IDs 775 to 841. In some embodiments, the TREM, TREM core fragment, or TREM fragment is coded by a sequence provided in Table 18, for example, any one of Sequence IDs 842 to 917. In some embodiments, a TREM, a TREM core fragment, or a TREM fragment is coded by a sequence provided in Table 19, for example, one of sequence numbers 918 to 992. In some embodiments, a TREM, a TREM core fragment, or a TREM fragment is coded by a sequence provided in Table 20, for example, one of sequence numbers 993 to 1078. In some embodiments, a TREM, a TREM core fragment, or a TREM fragment is coded by a sequence provided in Table 21, for example, one of sequence numbers 1079 to 1154. In some embodiments, a TREM, a TREM core fragment, or a TREM fragment is coded by a sequence provided in Table 22, for example, one of sequence numbers 1155 to 1187.

[0037] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a TREM, a TREM core fragment, or a TREM fragment as disclosed herein.

[0038] 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.

[0039] In some embodiments, the TREM, TREM core fragment, or TREM fragment does not exist in nature (for example, it is synthetic).

[0040] In one embodiment, TREM, TREM core fragment, or TREM fragment is prepared by cell-free solid-phase synthesis.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] In one embodiment of any of the methods disclosed herein, the TREM includes an anticodon that pairs with a stop codon.

[0052] 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.

[0053] 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.

[0054] Those skilled in the art will be able to recognize or confirm, by conventional experimentation alone, numerous equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be covered by the embodiments, figures, descriptions, examples, or claims listed below. [Brief explanation of the drawing]

[0055] [Figure 1] This schematic diagram shows the activity (log2 factor change) of modified TREM, including 2'-OMe, 2'-F, 2'-OME, 2'-deoxy, and PS modifications at each position along the exemplary TREM sequence (TREM-Arg-TGA), which is superior to unmodified TREM, as outlined in Example 11. [Modes for carrying out the invention]

[0056] Enumerated embodiments Enumerated Embodiments I 1. Arrangement of Equation A: [L1]-[ASt Domain 1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain 2] A TREM that includes, During the ceremony, Independently, the [L1] and [VL domains] are optional; [L1], [ASt domain 1], [L2]-[DH domain], [L3], [ACH domain], [VL domain], [TH domain], [L4], and one of [ASt domain 2] contains a nucleotide with a non-natural modification; Here: (a) TREM has the ability to assist in protein synthesis, be modified by synthetases, be bound by elongation factors, introduce amino acids into peptide chains, assist in elongation, or assist in initiation; (b) TREM comprises at least X consecutive nucleotides that have no unnatural modifications, where X is greater than 10; (c) at least 3 but less than all of the nucleotides of type (e.g., A, T, C, G, or U) contain the same unnatural modification; (d) at least X nucleotides of type (e.g., A, T, C, G, or U) that are free from unnatural modifications, where X = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50; (e) 5, 10, or 15 or fewer nucleotides of type (e.g., A, T, C, G, or U) containing unnatural modifications; and / or (f) TREM with 5, 10, or 15 or fewer nucleotides of type (e.g., A, T, C, G, or U) that are free from unnatural modifications.

[0057] 2. The TREM according to Embodiment 1, comprising the features shown in Embodiment 1(a).

[0058] 3. The TREM according to Embodiment 1, comprising the features shown in Embodiment 1(b).

[0059] 4. The TREM according to Embodiment 1, comprising the features shown in Embodiment 1(c).

[0060] 5. The TREM according to Embodiment 1, comprising the features shown in Embodiment 1(d).

[0061] 6. The TREM according to Embodiment 1, comprising the features shown in Embodiment 1(e).

[0062] 7. The TREM according to Embodiment 1, comprising the features shown in Embodiment 1(f).

[0063] 8. The TREM according to Embodiment 1, comprising all the features shown in Embodiments 1(a) to (f).

[0064] 9. A TREM according to any one of Embodiments 1 to 8, wherein the domain, including unnatural modifications, has a function, for example, the domain function described herein.

[0065] 10. A TREM according to any one of Embodiments 1 to 8, including [L1].

[0066] 11. A TREM according to any one of Embodiments 1 to 8, including a [VL domain].

[0067] 12. The TREM according to any one of Embodiments 1 to 8, wherein [L1] is a linker containing a nucleotide having a non-natural modification.

[0068] 13. A TREM according to any one of Embodiments 1 to 8, wherein the [ASt domain 1 (AstD1)] comprises a nucleotide having an unnatural modification.

[0069] 14. The TREM according to any one of Embodiments 1 to 8, wherein [L2] is a linker containing a nucleotide having a non-natural modification.

[0070] 15. A TREM according to any one of Embodiments 1 to 8, wherein the [DH domain (DHD)] comprises a nucleotide having an unnatural modification.

[0071] 16. The TREM according to any one of Embodiments 1 to 8, wherein [L3] is a linker containing a nucleotide having a non-natural modification.

[0072] 17. A TREM according to any one of Embodiments 1 to 8, wherein the [ACH domain (ACHD)] comprises a nucleotide having an unnatural modification.

[0073] 18. A TREM according to any one of Embodiments 1 to 8, wherein the [VL domain (VLD)] comprises a nucleotide having an unnatural modification.

[0074] 19. A TREM according to any one of Embodiments 1 to 8, wherein the [TH domain (THD)] comprises a nucleotide having an unnatural modification.

[0075] 20. The TREM according to any one of Embodiments 1 to 8, wherein [L4] is a linker containing a nucleotide having a non-natural modification.

[0076] 21. A TREM according to any one of Embodiments 1 to 8, wherein the [ASt domain 2 (AStD2)] comprises a nucleotide having an unnatural modification.

[0077] 22. Array of Equation 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 A TREM core fragment containing, During the ceremony, x=1 and y=0 or 1; One of the [ASt domain 1], [ACH domain], and [ASt domain 2] contains a nucleotide with an unnatural modification; TREM is a TREM core fragment that assists protein synthesis; is modifiable by synthetases, can be bound by elongation factors, and has the ability to introduce amino acids into peptide chains, assisting elongation or initiation.

[0078] 23. TREM core fragment according to Embodiment 22, wherein AStD1 and AStD2 include an ASt domain (AStD).

[0079] 24. The TREM core fragment according to Embodiment 22, wherein the [ASt domain 1] and / or [ASt domain 2], which include unnatural modifications, have the ability to initiate or extend a polypeptide chain.

[0080] 25. The TREM core fragment according to Embodiment 22, wherein the [ACH domain] containing unnatural modifications has the ability to mediate pairing with codons.

[0081] 26. A TREM core fragment according to Embodiment 22, wherein 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].

[0082] 27. A TREM core fragment according to Embodiment 22, wherein 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].

[0083] 28. The TREM core fragment according to Embodiment 22, wherein y=1 for linker[L1] and L1 comprises a nucleotide having a non-natural modification.

[0084] 29. The TREM core fragment according to Embodiment 22, wherein y=1 for linker [L2] and L2 comprises a nucleotide having a non-natural modification.

[0085] 30. The TREM core fragment according to Embodiment 22, wherein y=1 for the [DH domain (DHD)], and the DHD comprises a nucleotide having a non-natural modification.

[0086] 31. The TREM core fragment according to Embodiment 30, wherein the DHD containing unnatural modifications has the ability to mediate recognition by aminoacyl-tRNA synthetase.

[0087] 32. The TREM core fragment according to Embodiment 22, wherein y=1 for linker [L3] and L3 comprises a nucleotide having a non-natural modification.

[0088] 33. The TREM core fragment according to Embodiment 22, wherein y=1 for the [VL domain (VLD)], and the VLD contains a nucleotide having a non-natural modification.

[0089] 34. The TREM core fragment according to Embodiment 22, wherein y=1 for the [TH domain (THD)], and the THD contains a nucleotide having an unnatural modification.

[0090] 35. The TREM core fragment according to Embodiment 34, wherein the THD containing unnatural modifications has the ability to mediate ribosome recognition.

[0091] 36. A TREM core fragment according to Embodiment 22, wherein y=1 for linker [L4] and L4 comprises a nucleotide having a non-natural modification.

[0092] 37. A TREM fragment containing the TREM portion, wherein the TREM is an array of formula A: [L1]-[ASt Domain 1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain 2] This includes, and here: TREM fragment, Unnatural modifications; and One, two, three, or all of the following, or any combination thereof: (a) TREM halves (e.g., 5' halves or 3' halves, resulting from cleavage in the anticodon sequence, e.g., in the ACH domain); (b) 5' fragments (e.g., fragments containing the 5' end, derived from cleavage in the DH domain or ACH domain); (c) 3' fragment (e.g., a fragment containing the 3' end, derived from a cleavage in the TH domain); or (d) Internal fragments (e.g., derived from a cleavage in any one of the ACH, DH, or TH domains) TREM fragments, including the one mentioned.

[0093] 38. The TREM according to Embodiment 37, wherein the TREM fragment comprises (a) a TREM half containing a nucleotide having an unnatural modification.

[0094] 39. The TREM according to Embodiment 37, wherein the TREM fragment comprises (b) a 5' fragment having a nucleotide with unnatural modifications.

[0095] 40. The TREM according to Embodiment 37, wherein the TREM fragment comprises (c) a 3' fragment containing a nucleotide having an unnatural modification.

[0096] 41. The TREM according to Embodiment 37, wherein the TREM fragment comprises (d) an internal fragment containing a nucleotide having an unnatural modification.

[0097] 42. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the TREM domain comprises a plurality of nucleotides each having a non-natural modification.

[0098] 43. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of AStD1 have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, or 7 or more.

[0099] 44. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X or fewer nucleotides of AStD1 have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, or 7 or more.

[0100] 45. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of AStD2 have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, or 7 or more.

[0101] 46. ​​A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X or fewer nucleotides of AStD2 have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, or 7 or more.

[0102] 47. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of ACHD have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more.

[0103] 48. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of ACHD have unnatural modifications, where X is 11, 12, 13, 14, 15, 16, or 17 or more.

[0104] 49. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X or fewer nucleotides of ACHD have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more.

[0105] 50. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X or fewer nucleotides of ACHD have unnatural modifications, where X is 11, 12, 13, 14, 15, or 16 or more.

[0106] 51. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of THD have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more.

[0107] 52. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of THD have unnatural modifications, where X is 11, 12, 13, 14, 15, 16, or 17 or more.

[0108] 53. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X or fewer nucleotides of THD have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more.

[0109] 54. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X or fewer nucleotides of THD have unnatural modifications, where X is 11, 12, 13, 14, 15, or 16 or more.

[0110] 55. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of DHD have unnatural modifications, where X is 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more.

[0111] 56. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of the DHD have unnatural modifications, where X is 11, 12, 13, 14, 15, 16, 17, 18, or 19 or more.

[0112] 57. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X or fewer nucleotides of the DHD have unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more.

[0113] 58. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X or fewer nucleotides of the DHD have unnatural modifications, where X is 11, 12, 13, 14, 15, 16, 17, or 18 or more.

[0114] 59. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of the VLD have unnatural modifications, where X is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 50, 100, 150, 200, or 271 or more.

[0115] 60. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein all of the nucleotides of AStD1, AStD2, ACHD, DHD, and / or THD have unnatural modifications.

[0116] 61. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of AStD1 and / or AStD2 are free from unnatural modifications, where X is 1, 2, 3, 4, 5, 6, or 7 or more.

[0117] 62. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of ACHD are free from unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 or more.

[0118] 63. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of THD are free from unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 or more.

[0119] 64. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of DHD are free from unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 or more.

[0120] 65. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of the VLD are free from unnatural modifications, where X is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 50, 100, 150, 200, or 271 or more.

[0121] 66. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the TREM linker L2 comprises two nucleotides each having a non-natural modification.

[0122] 67. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of the TREM linker are free from unnatural modifications, where X is equal to 1 or 2.

[0123] 68. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein each of the multiple TREM domains and linkers comprises a nucleotide having an unnatural modification.

[0124] 69. The TREM, TREM core fragment, or TREM fragment according to Embodiment 68, wherein one of the TREM domains and linker comprises multiple nucleotides each having a non-natural modification.

[0125] 70. A TREM, TREM core fragment, or TREM fragment according to any one of Embodiments 1 to 69, wherein the unnatural modification is a modification of the base or backbone of a nucleotide, for example, a modification selected from any one of Tables 5 to 9.

[0126] 71. A TREM, TREM core fragment, or TREM fragment according to any of Embodiments 1 to 70, wherein the non-natural modification is a base modification selected from the modifications listed in Table 5.

[0127] 72. A TREM, TREM core fragment, or TREM fragment according to any one of Embodiments 1 to 71, wherein the non-natural modification is a base modification selected from the modifications listed in Table 6.

[0128] 73. A TREM, TREM core fragment, or TREM fragment according to any of Embodiments 1 to 72, wherein the non-natural modification is a base modification selected from the modifications listed in Table 7.

[0129] 74. A TREM, TREM core fragment, or TREM fragment according to any of Embodiments 1 to 73, wherein the non-natural modification is a skeletal base modification selected from the modifications listed in Table 8.

[0130] 75. A TREM, TREM core fragment, or TREM fragment according to any of Embodiments 1 to 74, wherein the non-natural modification is a skeletal modification selected from the modifications listed in Table 9.

[0131] 76. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, comprising a first type nucleotide including unnatural modifications.

[0132] 77. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, comprising a first type nucleotide and a second type nucleotide including unnatural modifications.

[0133] 78. The TREM, TREM core fragment, or TREM fragment according to Embodiment 77, wherein the unnatural modification of the first type of nucleotide and the unnatural modification of the second type of nucleotide are the same unnatural modification.

[0134] 79. The TREM, TREM core fragment, or TREM fragment according to Embodiment 77, wherein the unnatural modification of the first type of nucleotide and the unnatural modification of the second type of nucleotide are different unnatural modifications.

[0135] 80. A TREM, TREM core fragment, or TREM fragment according to Embodiment 76 or 77, wherein the first type of nucleotide is selected from A, T, C, G, or U.

[0136] 81. The TREM, TREM core fragment, or TREM fragment according to Embodiment 76 or 77, wherein the second type of nucleotide is selected from A, T, C, G, or U.

[0137] 82. A TREM, TREM core fragment, or TREM fragment according to Embodiment 76 or 77, wherein the first type of nucleotide is A.

[0138] 83. A TREM, TREM core fragment, or TREM fragment according to Embodiment 76 or 77, wherein the first type of nucleotide is G.

[0139] 84. A TREM, TREM core fragment, or TREM fragment according to Embodiment 76 or 77, wherein the first type of nucleotide is C.

[0140] 85. The TREM core fragment or TREM fragment according to Embodiment 76 or 77, wherein the first type of nucleotide is T.

[0141] 86. A TREM, TREM core fragment, or TREM fragment according to Embodiment 76 or 77, wherein the first type of nucleotide is U.

[0142] 87. The TREM, TREM core fragment, or TREM fragment according to Embodiment 77, wherein the first type of nucleotide is A, and the second type of nucleotide is selected from T, C, G, or U.

[0143] 88. The TREM, TREM core fragment, or TREM fragment according to Embodiment 77, wherein the first type of nucleotide is G, and the second type of nucleotide is selected from T, C, A, or U.

[0144] 89. The TREM, TREM core fragment, or TREM fragment according to Embodiment 77, wherein the first type of nucleotide is C, and the second type of nucleotide is selected from T, A, G, or U.

[0145] 90. The TREM, TREM core fragment, or TREM fragment according to Embodiment 77, wherein the first type of nucleotide is T, and the second type of nucleotide is selected from A, C, G, or U.

[0146] 91. The TREM, TREM core fragment, or TREM fragment according to Embodiment 77, wherein the first type of nucleotide is U, and the second type of nucleotide is selected from T, C, G, or A.

[0147] 92. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the non-natural modification is in purine (A or G).

[0148] 93. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the non-natural modification is not in purine (A or G).

[0149] 94. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the unnatural modification is in a pyrimidine (U, T, or C).

[0150] 95. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the non-natural modification is not in a pyrimidine (U, T, or C).

[0151] 96. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the DHD has a first sequence, a second sequence, and a third sequence, and optionally, for example, under physiological conditions, the first sequence and the third sequence form a stem and the second sequence forms a loop.

[0152] 97. TREM, TREM core fragment, or TREM fragment according to Embodiment 96, wherein the DHD includes unnatural modifications in the first or third sequence, for example, in the stem.

[0153] 98. The TREM, TREM core fragment, or TREM fragment according to Embodiment 96, wherein the DHD includes unnatural modifications in the second sequence, for example, in a loop.

[0154] 100.ACHD having a first sequence, a second sequence and a third sequence, wherein optionally, for example, under physiological conditions, the first sequence and the third sequence form a stem and the second sequence forms a loop, the TREM according to any one of Embodiments 1 to 8, the TREM core fragment according to Embodiment 22, or the TREM fragment according to Embodiment 37.

[0155] 101. The TREM, TREM core fragment, or TREM fragment according to Embodiment 100, wherein ACHD includes a non-natural modification in the first or third sequence, for example, in the stem.

[0156] 102. The TREM, TREM core fragment, or TREM fragment according to Embodiment 100, wherein ACHD includes unnatural modifications in the second sequence, for example, in a loop.

[0157] 103. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the THD has a first sequence, a second sequence, and a third sequence, and optionally, for example, under physiological conditions, the first sequence and the third sequence form a stem and the second sequence forms a loop.

[0158] 104. The TREM, TREM core fragment, or TREM fragment according to Embodiment 103, wherein THD includes unnatural modifications in the first or third sequence, for example, in the stem.

[0159] 105. The TREM, TREM core fragment, or TREM fragment according to Embodiment 103, wherein the THD includes unnatural modifications in the second sequence, for example, in a loop.

[0160] 106. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein VLD includes a variable region having 1 to 271 nucleotides.

[0161] 107. A TREM comprising at least X consecutive nucleotides without unnatural modifications, where X is greater than 10, as described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37.

[0162] 108. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least 3 but fewer than all of the nucleotides of type (e.g., A, T, C, G, or U) contain the same unnatural modification.

[0163] 109. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein at least X nucleotides of type (e.g., A, T, C, G, or U) are free from unnatural modifications, where X = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0164] 110. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein 5, 10, or 15 or fewer of type (e.g., A, T, C, G, or U) include unnatural modifications.

[0165] 111. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein 5, 10, or 15 or fewer of type (e.g., A, T, C, G, or U) do not contain unnatural modifications.

[0166] A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein X is 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.

[0167] 113. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, which recognizes the codons shown in Table 8 or Table 9.

[0168] 114. A TREM which is a family TREM, such as the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37.

[0169] 115. A TREM which is a non-family TREM, the TREM core fragment described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37.

[0170] 116. A TREM, TREM core fragment, or TREM fragment according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the TREM, TREM core fragment, or TREM fragment is coded by the sequence provided in Table 1, for example, one of SEQ ID NOs: 1 to 451.

[0171] 117. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the TREM, TREM core fragment, or TREM fragment is coded by a consensus sequence selected from any one of sequence numbers 562 to 621.

[0172] 118. A TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, wherein the TREM, TREM core fragment, or TREM fragment is coded by a consensus sequence selected from any one of sequence numbers 622 to 1187.

[0173] 119. A pharmaceutical composition comprising a TREM described in any one of Embodiments 1 to 8, a TREM core fragment described in Embodiment 22, or a TREM fragment described in Embodiment 37.

[0174] 120. The pharmaceutical composition according to Embodiment 119, comprising pharmaceutically acceptable components, for example, excipients.

[0175] 121. A lipid nanoparticle formulation comprising TREM as described in any one of Embodiments 1 to 8, TREM core fragment as described in Embodiment 22, or TREM fragment as described in Embodiment 37.

[0176] 122. A method for producing a TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, comprising linking a first nucleotide to a second nucleotide to form a TREM.

[0177] 123. The method according to Embodiment 122, wherein the TREM, TREM core fragment, or TREM fragment is synthetic (e.g., not found in nature).

[0178] 124. The method according to Embodiment 122 or 123, wherein the synthesis is performed in vitro.

[0179] 125. The method according to Embodiment 122, wherein TREM, TREM core fragment, or TREM fragment is prepared by cell-free solid-phase synthesis.

[0180] 126. Cells comprising a TREM as described in any one of Embodiments 1 to 8, a TREM core fragment as described in Embodiment 22, or a TREM fragment as described in Embodiment 37.

[0181] 127. Cells containing TREM, TREM core fragment, or TREM fragment prepared according to the method described in Embodiment 122.

[0182] 128. A method for regulating the intracellular tRNA pool, To provide a TREM according to any one of Embodiments 1 to 8, a TREM core fragment according to Embodiment 22, or a TREM fragment according to Embodiment 37, and The cells are brought into contact with TREM, TREM core fragments, or TREM fragments. A method that involves thereby regulating the intracellular tRNA pool.

[0183] 129. A method for bringing cells, tissues, or subjects into contact with a TREM described in any one of Embodiments 1 to 8, a TREM core fragment described in Embodiment 22, or a TREM fragment described in Embodiment 37, Cells, tissues, or subjects are brought into contact with TREM, TREM core fragments, or TREM fragments. A method comprising bringing cells, tissues, or objects into contact with a TREM, a TREM core fragment, or a TREM fragment.

[0184] 130. A method for providing TREM, TREM core fragments, or TREM fragments to cells, tissues, or subjects using TREM, Cells, tissues, or subjects are brought into contact with the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37. A method comprising providing a TREM, a TREM core fragment, or a TREM fragment to cells, tissue, or a subject.

[0185] 131. A method for forming a TREM, a TREM core fragment, or cells, tissues, or objects in contact with a TREM fragment, Cells, tissues, or subjects are brought into contact with the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37. A method comprising thereby forming a TREM, a TREM core fragment, or cells, tissues, or an object in contact with a TREM fragment.

[0186] 132. A method of using TREM, TREM core fragments, or TREM fragments, Cells, tissues, or subjects are brought into contact with the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37. This includes methods such as using TREM.

[0187] 133. A method for applying TREM, TREM core fragment, or TREM fragment to cells, tissue, or subject, Cells, tissues, or subjects are brought into contact with the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37. A method comprising applying a TREM, a TREM core fragment, or a TREM fragment to cells, tissue, or a subject.

[0188] 134. A method of exposing cells, tissues, or subjects to TREM, Cells, tissues, or subjects are brought into contact with the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37. A method comprising exposing cells, tissues, or subjects to TREM, TREM core fragments, or TREM fragments.

[0189] 135. A method for forming a TREM, a TREM core fragment, or a mixture of TREM fragments and cells, tissues, or a subject, Cells, tissues, or subjects are brought into contact with the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37. A method comprising thereby forming a TREM, a TREM core fragment, or a mixture of TREM fragments and cells, tissues, or a subject.

[0190] 136. A method for delivering TREM, TREM core fragments, or TREM fragments to cells, tissues, or subjects, A method comprising providing cells, tissues, or subjects, and contacting the cells, tissues, or subjects with a TREM described in any one of Embodiments 1 to 8, a TREM core fragment described in Embodiment 22, or a TREM fragment described in Embodiment 37.

[0191] 137. Methods for regulating metabolism, for example, the translational capacity of organelles, for example, ex vivo methods, A method comprising providing a preparation of a cellular organelle, such as a mitochondria or chloroplast, and contacting the organelle with a TREM described in any one of Embodiments 1 to 8, a TREM core fragment described in Embodiment 22, or a TREM fragment described in Embodiment 37.

[0192] 138. A method for treating a subject, for example, by regulating metabolism in the subject, for example, by regulating the translational capacity of cells, The subject is provided with TREM as described in any one of Embodiments 1 to 8, TREM core fragment as described in Embodiment 22, or TREM fragment as described in Embodiment 37, for example, administered. A method that includes treating the subject.

[0193] 139. A method for regulating an intracellular tRNA pool comprising an endogenous open reading frame (ORF) containing 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 described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37, 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, A method wherein 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.

[0194] 140. A method for regulating the tRNA pool in a subject having an endogenous open reading frame (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 the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37, 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, A method wherein 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.

[0195] 141. A method for regulating the tRNA pool in a subject having an endogenous open reading frame (ORF) containing a codon containing a synonymous mutation (synonymous mutation codon or SMC), To provide a composition comprising a TREM described in any one of Embodiments 1 to 8, a TREM core fragment described in Embodiment 22, or a TREM fragment described in Embodiment 37, 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. A method that includes thereby regulating the tRNA pool in a target.

[0196] 142. A method for regulating an intracellular tRNA pool containing an endogenous open reading frame (ORF) containing a codon containing a synonymous mutation (synonymous mutation codon or SMC), To provide a composition comprising a TREM described in any one of Embodiments 1 to 8, a TREM core fragment described in Embodiment 22, or a TREM fragment described in Embodiment 37, 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. A method that involves thereby regulating the intracellular tRNA pool.

[0197] 143. A method for regulating the expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) containing a mutated codon, and the method is The cells are brought into contact with a composition comprising the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37, 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. A method wherein the TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with a mutated codon.

[0198] 144. A method for regulating the expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) containing a mutated codon, and the method is The subject is brought into contact with a composition comprising the TREM described in any one of Embodiments 1 to 8, the TREM core fragment described in Embodiment 22, or the TREM fragment described in Embodiment 37, 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, A method wherein the TREM, TREM core fragment, or TREM fragment has an anticodon that pairs with a mutated codon.

[0199] 145. The method according to Embodiment 143 or 144, wherein the mutation in the ORF is a nonsense mutation resulting in an immature stop codon selected from, for example, UAA, UGA, or UAG.

[0200] 146. The method according to Embodiment 143 or 144, wherein TREM comprises an anticodon that pairs with a stop codon.

[0201] Enumerated Embodiments II 1000. A TREM comprising a nucleotide containing a non-natural modification (at a position specified herein) or a nucleotide lacking a non-natural modification (at a position specified herein).

[0202] 1001. The following structure: A TREM according to Embodiment 1000, including [L1]-[ASt Domain 1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain 2].

[0203] 1002. Sequence of formula A: [L1]-[ASt Domain 1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain 2] A TREM that includes, During the ceremony, Independently, the [L1] and [VL domains] are optional; [L1], [ASt domain 1], [L2]-[DH domain], [L3], [ACH domain], [VL domain], [TH domain], [L4], and one of [ASt domain 2] contains a nucleotide with a non-natural modification; Here: (a) TREM has the ability to (i) assist in protein synthesis, (ii) be modified by synthetases, (iii) be bound by elongation factors, (iv) introduce amino acids into peptide chains, (v) assist in elongation, or (vi) assist in initiation; (b) TREM contains X1 consecutive nucleotides without unnatural modifications, where X1 is 3, 4, 5, 6, 7, 8, 9, 10 or more; (c)TREM contains X2 non-natural modifications, where X2 is 2, 3, 4 or more; (d) TREM contains X3 different non-natural modifiers, where X3 is 2, 3, 4 or more; (e) Three nucleotides, but less than all of the nucleotides of type (e.g., A, T, C, G, or U) contain the same unnatural modification; (f) X4 nucleotides of type (e.g., A, T, C, G, or U) without unnatural modifications, where X4 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 or more; (g) 5, 10, or 15 or fewer nucleotides of type (e.g., A, T, C, G, or U) containing unnatural modifications; and / or (h) TREM having 5, 10, or 15 or fewer nucleotides of type (e.g., A, T, C, G, or U) without unnatural modifications; and / or the ACH domain containing a non-extended anticodon.

[0204] 1003. (a) The TREM according to Embodiment 1000 or 1001, wherein the TREM has the ability to (i) assist in protein synthesis, (ii) be modified by synthetase, (iii) be bound by elongation factors, (iv) introduce amino acids into a peptide chain, (v) assist in elongation, or (vi) assist in initiation.

[0205] 1004. (b) The TREM according to any one of Embodiments 1000 to 1003, wherein the TREM comprises X1 consecutive nucleotides without unnatural modifications, and X1 is 10 or more.

[0206] 1005. A TREM according to any one of embodiments 1000 to 1004, wherein the TREM comprises X2 non-natural modifications, where X2 is 2, 3, 4, or more.

[0207] 1006. (c) The TREM according to any one of Embodiments 1000 to 1005, wherein the TREM comprises X3 different non-natural modifiers, where X3 is 2, 3, 4, or more.

[0208] 1007. (d) A TREM according to any one of Embodiments 1000 to 1006, wherein three nucleotides, but less than all of the nucleotides of type (e.g., A, T, C, G, or U) contain the same unnatural modification.

[0209] 1008. (e) A TREM according to any one of Embodiments 1000 to 1007, wherein X4 nucleotides of type (e.g., A, T, C, G, or U) are free from unnatural modifications, where X4 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more.

[0210] 1009. (f) A TREM according to any one of Embodiments 1000 to 1008, wherein 5, 10, or 15 or fewer nucleotides of type (e.g., A, T, C, G, or U) include unnatural modifications.

[0211] 1010. (g) A TREM according to any one of Embodiments 1000 to 1009, wherein 5, 10, or 15 or fewer nucleotides of type (e.g., A, T, C, G, or U) are free from unnatural modifications; and / or the ACH domain contains a non-extended anticodon.

[0212] 1011. A TREM according to any one of embodiments 1000 to 1010, wherein the ACH domain contains or does not contain an elongated anticodon.

[0213] 1012. A TREM fragment containing the portion of TREM, where TREM is an array of formula A: [L1]-[ASt Domain 1]-[L2]-[DH Domain]-[L3]-[ACH Domain]-[VL Domain]-[TH Domain]-[L4]-[ASt Domain 2] This includes, and here: TREM fragment, Unnatural modifications; and One, two, three, or all of the following, or any combination thereof: (a) TREM halves (e.g., 5' halves or 3' halves, resulting from cleavage in the anticodon sequence, e.g., in the ACH domain); (b) 5' fragments (e.g., fragments containing the 5' end, derived from cleavage in the DH domain or ACH domain); (c) 3' fragment (e.g., a fragment containing the 3' end, derived from a cleavage in the TH domain); or (d) Internal fragments (e.g., derived from a cleavage in any one of the ACH, DH, or TH domains) TREM fragments, including the one mentioned.

[0214] 1013. A TREM or TREM fragment according to any one of embodiments 1000 to 1012, comprising a nucleotide sugar moiety (2'-modification) or an unnatural modification to the TREM skeleton.

[0215] 1014. A TREM or TREM fragment according to any one of embodiments 1000 to 1013, comprising a nucleotide with a 2' unnatural modification in the sugar portion.

[0216] 1015. A TREM or TREM fragment according to any one of embodiments 1000 to 1014, wherein a nucleotide corresponding to any of nucleotides 1 to 76 of SEQ ID NO: 622, nucleotides 1 to 85 of SEQ ID NO: 993, or nucleotides 1 to 75 of SEQ ID NO: 1079 is modified.

[0217] 1016. A TREM or TREM fragment according to Embodiments 1000-1015, wherein the nucleotide is located in ASt domain 1.

[0218] 1017. A TREM or TREM fragment according to embodiments 1000-1016, wherein the nucleotide is located in the DH domain.

[0219] 1018. A TREM or TREM fragment according to Embodiments 1000-1017, wherein the nucleotide is located in the ACH domain.

[0220] 1019. A TREM or TREM fragment according to Embodiments 1000-1018, wherein the nucleotide is located in the VL domain.

[0221] 1020. A TREM or TREM fragment according to embodiments 1000-1019, wherein the nucleotide is located in the TH domain.

[0222] 1021. A TREM or TREM fragment according to Embodiments 1000-1020, wherein the nucleotide is located in ASt domain 2.

[0223] 1022. A TREM or TREM fragment according to Embodiments 1000 to 10021, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0224] 1023. A TREM or TREM fragment according to Embodiments 1000 to 1022, wherein a nucleotide corresponding to any one of nucleotides 1, 2, 4, 6, 10, 12, 13, 17, 18, 20, 22, 29, 30, 42, 43, 45, 50, 52, 56, 59, 61, 65, 66, 68, 69, 71, 72, and 73 of SEQ ID NO: 622 is modified.

[0225] 1024. A TREM or TREM fragment according to Embodiments 1000 to 1022, wherein a nucleotide corresponding to any one of nucleotides 20, 29, 33, 40, 41, 44, 45, 48, 49, 50, 52, 53, 54, 56, 59, 61, 62, 63, 65, 67, 68, 69, 71, 72, 75, and 76 of SEQ ID NO: 622 is modified.

[0226] 1025. A TREM or TREM fragment according to Embodiments 1000 to 1022, wherein a nucleotide corresponding to any one of nucleotides 1, 4, 14, 15, 16, 17, 20, 29, 44, 45, 47, 49, 50, 52, 54, 56, 57, 59, 65, 72, and 73 of SEQ ID NO: 622 is modified.

[0227] 1026. A TREM or TREM fragment according to Embodiments 1000 to 1022, wherein a nucleotide corresponding to any one of nucleotides 3, 4, 5, 6, 14, 15, 16, 20, 22, 23, 33, 54, 59, 62, 63, 72, and 76 of SEQ ID NO: 622 is modified.

[0228] 1027. A TREM or TREM fragment according to Embodiments 1000 to 1022, wherein a nucleotide corresponding to any one of nucleotides 1, 2, 3, 9, 14, 15, 16, 17, 18, 19, 20, 21, 35, 37, 38, 44, 45, 46, 52, 54, 55, 56, 57, 58, 73, and 74 of SEQ ID NO: 622 is modified.

[0229] 1028. A TREM or TREM fragment according to Embodiments 1000 to 1022, wherein a nucleotide corresponding to any one of nucleotides 1, 17, 18, 20, 29, 30, 50, 52, and 73 of Sequence ID No. 622 is modified.

[0230] 1029. A TREM or TREM fragment according to Embodiments 1000 to 1022, wherein a nucleotide corresponding to one of nucleotides 1, 4, 5, 34, 38, 39, 61, 79, 80, and 82 of Sequence ID No. 993 is modified.

[0231] 1030. A TREM or TREM fragment according to Embodiments 1000 to 1022, wherein a nucleotide corresponding to any one of nucleotides 1, 4, 12, 13, 17, 18, 23, 28, 29, 30, 38, 39, 41, 44, 48, 49, 51, 52, 53, 58, 60, 61, 63, 64, 65, 66, 68, 69, 71, 72, 73, 74, and 75 of SEQ ID NO: 1079 is modified.

[0232] 1031.2' The TREM or TREM fragment according to Embodiments 1000 to 1014, wherein the unnatural modification comprises an ester, a halo, hydrogen, or an alkyl group.

[0233] 1032.2'Non-natural modification comprising a 2'-OMe moiety, TREM or TREM fragment according to embodiments 1000-1014.

[0234] 1033. TREM or TREM fragment according to Embodiments 1000 to 1024, wherein the 2'-unnatural modification includes a 2'-MOE portion.

[0235] 1034.2'Non-natural modification comprising a 2'-halo (e.g., 2'-F or 2'Cl) as described in Embodiments 1000-1014, or TREM or TREM fragment.

[0236] 1035.2'A TREM or TREM fragment according to Embodiments 1000 to 1014, wherein the unnatural modification comprises a 2'-deoxy group (e.g., 2'-H).

[0237] 1036. A TREM or TREM fragment according to any of embodiments 1000 to 1035, comprising a nucleotide lacking unnatural modifications, for example, a nucleotide lacking 2' unnatural modifications in the sugar portion.

[0238] 1037. A TREM or TREM fragment according to any of Embodiments 1036, wherein the nucleotide corresponds to any of nucleotides 1 to 76 of SEQ ID NO: 622 and lacks unnatural modifications.

[0239] 1038. A TREM or TREM fragment according to Embodiment 1036, wherein the nucleotide is located in the ASt domain 1.

[0240] 1039. A TREM or TREM fragment according to Embodiment 1036, wherein the nucleotide is located in the DH domain.

[0241] 1040. A TREM or TREM fragment according to Embodiment 1036, wherein the nucleotide is located in the ACH domain.

[0242] 1041. A TREM or TREM fragment according to Embodiment 1036, wherein the nucleotide is located in the VL domain.

[0243] 1042. A TREM or TREM fragment according to Embodiment 1036, wherein the nucleotide is located in the TH domain.

[0244] 1043. A TREM or TREM fragment according to Embodiment 1036, wherein the nucleotide is located in the ASt domain 2.

[0245] 1044. A TREM or TREM fragment according to Embodiment 1036, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0246] 1045. A TREM or TREM fragment according to Embodiment 1036, wherein the nucleotide corresponds to any one of nucleotides 1 to 76 of SEQ ID NO: 622 and lacks unnatural modifications, such as 2' unnatural modifications in sugars.

[0247] 1046. A TREM or TREM fragment according to Embodiment 1036, wherein one of the nucleotides corresponding to any one of nucleotides 1 to 85 of SEQ ID NO: 993 lacks unnatural modifications, such as a 2' unnatural modification in a sugar.

[0248] The TREM or TREM fragment according to embodiment 1036, wherein the nucleotide corresponding to any one of nucleotides 1 to 75 of SEQ ID NO: 1079 lacks non-natural modification, such as 2'-non-natural modification in the sugar.

[0249] The TREM or TREM fragment according to any one of embodiments 1000 to 1047, comprising a nucleotide containing a 2'-OMe non-natural modification.

[0250] The TREM or TREM fragment according to any one of embodiments 1000 to 1048, wherein the nucleotide corresponding to any one of nucleotides 1 to 76 of SEQ ID NO: 622 is modified.

[0251] The TREM or TREM fragment according to any one of embodiments 1048 to 1049, wherein the nucleotide is in the ASt domain 1.

[0252] The TREM or TREM fragment according to any one of embodiments 1048 to 1049, wherein the nucleotide is in the DH domain.

[0253] The TREM or TREM fragment according to any one of embodiments 1048 to 1049, wherein the nucleotide is in the ACH domain.

[0254] The TREM or TREM fragment according to any one of embodiments 1048 to 1049, wherein the nucleotide is in the VL domain.

[0255] The TREM or TREM fragment according to any one of embodiments 1048 to 1049, wherein the nucleotide is in the TH domain.

[0256] The TREM or TREM fragment according to any one of embodiments 1048 to 1049, wherein the nucleotide is in the ASt domain 2.

[0257] 1056. A TREM or TREM fragment according to Embodiment 1048 or 1049, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0258] 1057. A TREM or TREM fragment according to any one of embodiments 1048 to 1056, wherein a nucleotide corresponding to any one of nucleotides 1, 2, 4, 6, 10, 12, 13, 17, 18, 20, 22, 29, 30, 42, 43, 45, 50, 52, 56, 59, 61, 65, 66, 68, 69, 71, 72, and 73 of SEQ ID NO: 622 is modified (for example, the sequences in Table 15).

[0259] 1058. A TREM or TREM fragment according to any of embodiments 1000 to 1047, comprising a nucleotide lacking unnatural modifications, for example, a nucleotide lacking a 2'OMe modification in the sugar portion.

[0260] 1059. A TREM or TREM fragment according to Embodiment 1058, wherein any nucleotide corresponding to nucleotides 1-76 of SEQ ID NO: 622 lacks unnatural modifications, for example, lacking a 2'OMe modification in the sugar portion.

[0261] 1060. A TREM or TREM fragment according to Embodiment 1058 or 1059, wherein the nucleotide is located in ASt domain 1.

[0262] 1061. A TREM or TREM fragment according to Embodiment 1058 or 1059, wherein the nucleotide is located in the DH domain.

[0263] 1062. A TREM or TREM fragment according to Embodiment 1058 or 1059, wherein the nucleotide is located in the ACH domain.

[0264] A TREM or TREM fragment according to embodiment 1058 or 1059, wherein 1063 nucleotides are located in the VL domain.

[0265] 1064. A TREM or TREM fragment according to Embodiment 1058 or 1059, wherein the nucleotide is located in the TH domain.

[0266] 1065. A TREM or TREM fragment according to Embodiment 1058 or 1059, wherein the nucleotide is located in ASt domain 2.

[0267] 1066. A TREM or TREM fragment according to Embodiment 1058 or 1059, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0268] 1067. A TREM or TREM fragment according to any one of embodiments 1000 to 1066, comprising a nucleotide containing a 2' halo, e.g., a 2' fluoro, or an unnatural modification in the sugar portion.

[0269] 1068. A TREM or TREM fragment according to Embodiment 1067, wherein the 2'-halo is 2'-fluoro.

[0270] 1069. A TREM or TREM fragment according to embodiment 1067 or 1068, wherein a nucleotide corresponding to any of nucleotides 1 to 76 of sequence number 622 is modified.

[0271] 1070. A TREM or TREM fragment according to Embodiment 1067 or 1068, wherein the nucleotide is located in ASt domain 1.

[0272] 1071. A TREM or TREM fragment according to Embodiment 1067 or 1068, wherein the nucleotide is located in the DH domain.

[0273] 1072. A TREM or TREM fragment according to Embodiment 1067 or 1068, wherein the nucleotide is located in the ACH domain.

[0274] 1073. A TREM or TREM fragment according to Embodiment 1067 or 1068, wherein the nucleotide is located in the VL domain.

[0275] 1074. The nucleotide is a TREM or TREM fragment according to embodiment 1067 or 1068, which is in the TH domain.

[0276] 1075. The nucleotide is a TREM or TREM fragment according to embodiment 1067 or 1068, which is in the ASt domain 2.

[0277] 1076. The nucleotide is a TREM or TREM fragment according to any one of embodiments 1067 or 1068, which is in a linker domain (for example, [L1], [L2], [L3], or [L4]).

[0278] 1077. The TREM or TREM fragment according to any one of embodiments 1067 - 1076, wherein a nucleotide corresponding to any one of nucleotides 20, 29, 33, 40, 41, 44, 45, 48, 49, 50, 52, 53, 54, 56, 59, 61, 62, 63, 65, 67, 68, 69, 71, 72, 75, and 76 of SEQ ID NO: 622 is modified.

[0279] 1078. The TREM or TREM fragment according to any one of embodiments 1000 - 1035, which contains nucleotides lacking non - natural modifications, for example, 2'-halo in the sugar moiety, for example, 2'-fluoro.

[0280] 1079. The TREM or TREM fragment according to embodiment 1078, wherein the 2'-halo is 2'-fluoro.

[0281] 1080. The TREM or TREM fragment according to embodiment 1078 or 1079, wherein the nucleotide corresponds to any one of nucleotides 1 - 76 of SEQ ID NO: 622 and lacks non - natural modifications.

[0282] 1081. The TREM or TREM fragment according to embodiment 1078 or 1079, wherein the nucleotide is in the ASt domain 1.

[0283] 1082. A TREM or TREM fragment according to Embodiment 1078 or 1079, wherein the nucleotide is located in the DH domain.

[0284] 1083. A TREM or TREM fragment according to Embodiment 1078 or 1079, wherein the nucleotide is located in the ACH domain.

[0285] 1084. A TREM or TREM fragment according to Embodiment 1078 or 1079, wherein the nucleotide is located in the VL domain.

[0286] 1085. A TREM or TREM fragment according to Embodiment 1078 or 1079, wherein the nucleotide is located in the TH domain.

[0287] 1086. A TREM or TREM fragment according to Embodiment 1078 or 1079, wherein the nucleotide is located in ASt domain 2.

[0288] 1087. A TREM or TREM fragment according to Embodiment 1078 or 1079, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0289] 1088. A TREM or TREM fragment according to any one of embodiments 1000 to 1013, wherein a nucleotide corresponding to any one of nucleotides 20, 29, 33, 40, 41, 44, 45, 48, 49, 50, 52, 53, 54, 56, 59, 61, 62, 63, 67, 68, 69, 71, 72, 75, and 76 of SEQ ID NO: 622 lacks unnatural modifications in the sugar, such as 2'-fluorounnatural modifications.

[0290] 1089. A TREM or TREM fragment according to any of embodiments 1000 to 1088, wherein the unnatural modification comprises a 2'-deoxynucleotide.

[0291] 1090. A TREM or TREM fragment according to Embodiment 1084, wherein the 2' deoxyribonucleotide corresponding to any of nucleotides 1 to 76 of SEQ ID NO: 622 is modified.

[0292] A TREM or TREM fragment according to Embodiment 1089 or 1090, wherein the 1091.2' deoxynucleotide is located in the ASt domain 1.

[0293] A TREM or TREM fragment according to Embodiment 1089 or 1090, wherein the 1092.2' deoxynucleotide is located in the DH domain.

[0294] A TREM or TREM fragment according to Embodiment 1089 or 1090, wherein the 1093.2' deoxyribonucleotide is located in the ACH domain.

[0295] A TREM or TREM fragment according to Embodiment 1089 or 1090, wherein the 1094.2' deoxyribonucleotide is located in the VL domain.

[0296] A TREM or TREM fragment according to Embodiment 1089 or 1090, wherein the 1095.2' deoxynucleotide is located in the TH domain.

[0297] The TREM or TREM fragment according to Embodiment 1089 or 1090, wherein the 1096.2' deoxyribonucleotide is located in the ASt domain 2.

[0298] 1097. A TREM or TREM fragment according to Embodiment 1089 or 1090, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0299] 1098. A TREM or TREM fragment according to Embodiment 1089 or 1090, wherein the nucleotide corresponding to any one of nucleotides 3, 4, 5, 6, 14, 15, 16, 20, 22, 23, 33, 54, 59, 62, 63, 72, and 76 of SEQ ID NO: 622 is a 2' deoxyribonucleotide.

[0300] A TREM or TREM fragment according to any one of embodiments 1000 to 1092, comprising a 1099.2'-OH nucleotide.

[0301] The TREM or TREM fragment according to Embodiment 1099, wherein the 1100.2'-OH nucleotide corresponds to any of nucleotides 1 to 76 of SEQ ID NO: 622.

[0302] 1101. A TREM or TREM fragment according to Embodiment 1099 or 1100, wherein a nucleotide is located in the ASt domain 1.

[0303] 1102. A TREM or TREM fragment according to any one of Embodiments 1099 or 1100-1100, wherein the nucleotide is located in the DH domain.

[0304] 1103. A TREM or TREM fragment according to either embodiment 1099 or 1100, wherein the nucleotide is located in the ACH domain.

[0305] 1104. A TREM or TREM fragment according to Embodiment 1099 or 1100, wherein the nucleotide is located in the VL domain.

[0306] 1105. A TREM or TREM fragment according to Embodiment 1099 or 1100, wherein the nucleotide is located in the TH domain.

[0307] 1106. A TREM or TREM fragment according to Embodiment 1099 or 1100, wherein the nucleotide is located in the ASt domain 2.

[0308] 1107. A TREM or TREM fragment according to Embodiment 1099 or 1100, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0309] 1109. A TREM or TREM fragment according to any one of embodiments 1000 to 1100, wherein the nucleotide corresponding to any one of nucleotides 3, 4, 5, 6, 14, 15, 16, 20, 22, 23, 33, 54, 59, 62, 63, 72, and 76 of SEQ ID NO: 622 is a 2'-OH nucleotide.

[0310] 1110. A TREM or TREM fragment according to any of embodiments 1000 to 1109, wherein the unnatural modification comprises a 2'-methoxyethyl (MOE) nucleotide.

[0311] 1111. A TREM or TREM fragment according to Embodiment 1110, wherein the nucleotide corresponds to any of nucleotides 1 to 76 of SEQ ID NO: 622.

[0312] A TREM or TREM fragment according to embodiment 1110 or 1111, wherein the 1112.2'-MOE nucleotide is located in the ASt domain 1.

[0313] A TREM or TREM fragment according to embodiment 1110 or 1111, wherein the 1113.2'-MOE nucleotide is located in the DH domain.

[0314] A TREM or TREM fragment according to embodiment 1110 or 1111, wherein the 1114.2'-MOE nucleotide is located in the ACH domain.

[0315] A TREM or TREM fragment according to embodiment 1110 or 1111, wherein the 1115.2'-MOE nucleotide is located in the VL domain.

[0316] A TREM or TREM fragment according to embodiment 1110 or 1111, wherein the 1116.2'-MOE nucleotide is located in the TH domain.

[0317] A TREM or TREM fragment according to embodiment 1110 or 1111, wherein the 1117.2'-MOE nucleotide is located in the ASt domain 2.

[0318] A TREM or TREM fragment according to Embodiment 1110 or 1111, wherein the 1118.2'-MOE nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0319] 1119. A TREM or TREM fragment according to any one of embodiments 1110 to 1118, wherein the nucleotide corresponding to any one of nucleotides 1, 4, 14, 15, 16, 17, 20, 29, 44, 45, 47, 49, 50, 52, 54, 56, 57, 59, 65, 72, and 73 of SEQ ID NO: 622 is a 2'-MOE nucleotide.

[0320] 1120. A TREM or TREM fragment according to any of embodiments 1000 to 1109, comprising a nucleotide lacking unnatural modifications, for example, a 2-MOE in the sugar moiety, for example, a nucleotide lacking unnatural modifications.

[0321] 1121. A TREM or TREM fragment according to Embodiment 1120, wherein the nucleotides correspond to any of nucleotides 1-76 of SEQ ID NO: 622 and lack unnatural modifications.

[0322] 1122. A TREM or TREM fragment according to Embodiment 1120 or 1121, wherein the nucleotide is located in the ASt domain 1.

[0323] 1123. A TREM or TREM fragment according to Embodiment 1120 or 1121, wherein the nucleotide is located in the DH domain.

[0324] 1124. A TREM or TREM fragment according to Embodiment 1120 or 1121, wherein the nucleotide is located in the ACH domain.

[0325] 1125. A TREM or TREM fragment according to Embodiment 1120 or 1121, wherein the nucleotide is located in the VL domain.

[0326] 1126. A TREM or TREM fragment according to Embodiment 1120 or 1121, wherein the nucleotide is located in the TH domain.

[0327] 1127. A TREM or TREM fragment according to Embodiment 1120 or 1121, wherein the nucleotide is located in the ASt domain 2.

[0328] 1128. A TREM or TREM fragment according to Embodiment 1120 or 1121, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0329] 1129. A TREM or TREM fragment according to any one of embodiments 1120 to 1128, wherein the nucleotide corresponds to one of nucleotides 1, 4, 14, 15, 16, 17, 20, 29, 44, 45, 47, 49, 50, 52, 54, 56, 57, 59, 65, 72, and 73 of SEQ ID NO: 622, and lacks a 2'-MOE nucleotide.

[0330] 1130. A TREM or TREM fragment according to any of embodiments 1000 to 1129, comprising a modified skeleton, for example, modification of a phosphate moiety bonded to the 5' or 3' carbon of the sugar moiety of a nucleotide.

[0331] A TREM or TREM fragment according to embodiment 1130, wherein the phosphate moiety bonded to the 1131.5' carbon is modified.

[0332] A TREM or TREM fragment according to Embodiment 1130, wherein the phosphate moiety bonded to the 1132.3' carbon is modified.

[0333] 1133. A TREM or TREM fragment according to Embodiment 1130, wherein the modification includes a phosphothioate moiety.

[0334] 1134. A TREM or TREM fragment according to embodiments 1130 to 1133, wherein a nucleotide corresponding to any of nucleotides 1 to 76 of sequence number 622 is modified.

[0335] 1135. A TREM or TREM fragment according to Embodiments 1130-1133, wherein a modified nucleotide is located in the ASt domain 1.

[0336] 1136. A TREM or TREM fragment according to embodiments 1130-1133, wherein a modified nucleotide is located in the DH domain.

[0337] 1137. A TREM or TREM fragment according to Embodiments 1130-1133, wherein a modified nucleotide is located in the ACH domain.

[0338] 1138. A TREM or TREM fragment according to embodiments 1130-1133, wherein a modified nucleotide is located in the VL domain.

[0339] 1139. A TREM or TREM fragment according to embodiments 1130-1133, wherein a modified nucleotide is located in the TH domain.

[0340] 1140. A TREM or TREM fragment according to embodiments 1130-1133, wherein a modified nucleotide is located in the ASt domain 2.

[0341] 1141. A TREM or TREM fragment according to any of embodiments 1130 to 1133, wherein the nucleotide is located in a linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0342] 1142. A TREM or TREM fragment according to Embodiments 1130 to 1133, wherein a nucleotide corresponding to any one of nucleotides 1, 2, 3, 9, 14, 15, 16, 17, 18, 19, 20, 21, 35, 37, 38, 44, 45, 46, 52, 54, 55, 56, 57, 58, 73, and 74 of SEQ ID NO: 622 is modified, for example, by a phosphorothioate moiety.

[0343] 1142. A TREM or TREM fragment according to Embodiments 1130 to 1141, wherein a nucleotide corresponding to any one of nucleotides 14, 15, 16, 17, 18, 20, 44, 45, 47, 54, 56, 57, and 59 of SEQ ID NO: 622 is modified, for example, by a phosphorothioate moiety.

[0344] 1143. TREM or TREM fragment according to embodiments 1000 to 1142, which has a skeletal modification, for example, lacking a phosphorothioate moiety.

[0345] 1144. A TREM or TREM fragment according to Embodiment 1143, wherein an unmodified nucleotide corresponds to any of nucleotides 1 to 76 of SEQ ID NO: 622.

[0346] 1145. A TREM or TREM fragment according to Embodiment 1143, wherein an unmodified nucleotide is located in the ASt domain 1.

[0347] 1146. A TREM or TREM fragment according to Embodiment 1143, wherein an unmodified nucleotide is located in the DH domain.

[0348] 1147. A TREM or TREM fragment according to Embodiment 1143, wherein an unmodified nucleotide is located in the ACH domain.

[0349] 1148. A TREM or TREM fragment according to Embodiment 1143, wherein an unmodified nucleotide is located in the VL domain.

[0350] 1149. A TREM or TREM fragment according to Embodiment 1143, wherein an unmodified nucleotide is located in the TH domain.

[0351] 1150. A TREM or TREM fragment according to Embodiment 1143, wherein an unmodified nucleotide is located in the ASt domain 2.

[0352] 1151. A TREM or TREM fragment according to Embodiment 1143, wherein an unmodified nucleotide is located in the linker domain (e.g., [L1], [L2], [L3], or [L4]).

[0353] 1152. A TREM or TREM fragment according to any one of embodiments 1000 to 1151, wherein the nucleotide corresponding to any one of nucleotides 1, 2, 3, 9, 14, 15, 16, 17, 18, 19, 20, 21, 35, 37, 38, 44, 45, 46, 52, 54, 55, 56, 57, 58, 73, and 74 of SEQ ID NO: 622 is not skeletally modified.

[0354] 1153. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 15 are modified with 2'-O Me.

[0355] 1154. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 15 are modified with 2'-O Me.

[0356] 1155. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 15 are modified with 2'-O Me.

[0357] 1156. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 15 are not modified.

[0358] 1157. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 15 are not modified.

[0359] 1158. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 15 are not modified.

[0360] 1159. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 21 are modified with 2'-O Me.

[0361] 1160. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 21 are modified with 2'-O Me.

[0362] 1161. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 21 are modified with 2'-O Me.

[0363] 1162. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 21 are not modified.

[0364] 1163. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 21 are not modified.

[0365] 1164. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 21 are not modified.

[0366] 1165. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 22 are modified with 2'-O Me.

[0367] 1166. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 22 are modified with 2'-O Me.

[0368] 1167. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 22 are modified with 2'-O Me.

[0369] 1168. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 22 are not modified.

[0370] 1169. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 22 are not modified.

[0371] 1170. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 22 are not modified.

[0372] 1171 A TREM or TREM fragment according to any of embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 17 are modified with 2'-MOE.

[0373] 1172. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 17 are modified with 2'-MOE.

[0374] 1173. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 17 are modified with 2'-MOE.

[0375] 1174. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 17 are not modified.

[0376] 1175. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 17 are not modified.

[0377] 1176. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 17 are not modified.

[0378] 1177. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 16 are modified with 2'-fluoropolymer.

[0379] 1178. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the sequence in Table 16 are modified with 2'-fluoropolymer.

[0380] 1179. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the sequence in Table 16 are modified with 2'-fluoropolymer.

[0381] 1180. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 16 are not modified.

[0382] 1181. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 16 are not modified.

[0383] 1182. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 16 are not modified.

[0384] 1183. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the sequence in Table 18 are modified to be 2'-deoxy.

[0385] 1184. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the sequence in Table 18 are modified to be 2'-deoxy.

[0386] 1185. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the sequence in Table 18 are modified to be 2'-deoxy.

[0387] 1186. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 18 are not modified.

[0388] 1187. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 18 are not modified.

[0389] 1188. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 18 are not modified.

[0390] 1189. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the position corresponding to the modification position having a value of 3 for 100 nm in the sequence in Table 19 contains a phosphorothate.

[0391] 1190. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the sequence in Table 19 contain phosphorotate.

[0392] 1191. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the sequence in Table 19 contain phosphorotate.

[0393] 1192. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 3 per 100 nm in the arrangement in Table 19 are not modified.

[0394] 1193. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 2 per 100 nm in the arrangement in Table 19 are not modified.

[0395] 1194. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the positions corresponding to the modification positions having a value of 1 per 100 nm in the arrangement in Table 19 are not modified.

[0396] 1195. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the TREM contains an anticodon specific to an amino acid from Table 1.

[0397] 1196. A TREM or TREM fragment according to any of Embodiments 1000 to 1152, wherein the TREM contains the anticodons listed in Table 1.

[0398] 1197. TREM or TREM fragment according to any of embodiments 1000 to 1196, comprising first and second non-natural modifications.

[0399] 1198. TREM or TREM fragment according to Embodiment 1197, comprising a third non-natural modification.

[0400] 1199. TREM or TREM fragment according to Embodiment 1197 or 1198, comprising first and second unnatural modifications which are the same unnatural modification.

[0401] 1200. TREM or TREM fragment according to Embodiment 1197 or 1198, comprising first and second unnatural modifications which are different unnatural modifications.

[0402] 1201. A TREM or TREM fragment according to Embodiment 1197 or 1198, comprising first and second unnatural modifications located on the same nucleotide.

[0403] 1202. The TREM or TREM fragment according to Embodiment 1197 or 1198, wherein the first and second unnatural modifications are located on different nucleotides.

[0404] 1203. The TREM or TREM fragment according to Embodiment 1197 or 1198, wherein the first and second unnatural modifications are located in the same domain.

[0405] 1204. The TREM or TREM fragment according to Embodiment 1197 or 1198, wherein the first and second unnatural modifications are located in different domains.

[0406] 1205. A TREM or TREM fragment according to any one of Embodiments 1000 to 1204, wherein the domain including a non-natural modification has a function, for example, a domain function described herein.

[0407] 1206. A TREM or TREM fragment according to any of Embodiments 1000 to 1205, wherein the TREM has at least X% sequence identity with a sequence described herein, for example, SEQ ID NO: 622, SEQ ID NO: 993, or SEQ ID NO: 1079, or a consensus sequence disclosed herein from, for example, Table 9 or 10, where X = 60, 70, 75, 80, 85, 90, or 95.

[0408] 1207. A TREM or TREM fragment according to Embodiment 1206, wherein X = 60.

[0409] 1208. A TREM or TREM fragment according to Embodiment 1206, wherein X = 70.

[0410] 1209. A TREM or TREM fragment according to Embodiment 1206, wherein X = 75.

[0411] 1210. A TREM or TREM fragment according to Embodiment 1206, wherein X = 80.

[0412] 1211. A TREM or TREM fragment according to Embodiment 1206, wherein X = 85.

[0413] 1212. A TREM or TREM fragment according to Embodiment 1206, wherein X = 90.

[0414] 1213. A TREM or TREM fragment according to Embodiment 1206, wherein X = 95.

[0415] 1214. A TREM or TREM fragment according to any of Embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to a modified position in any row of Tables 15 to 22.

[0416] 1215. A TREM or TREM fragment according to any of Embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to the modified position in the row of Table 15.

[0417] 1216. A TREM or TREM fragment according to any of Embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to the modified position in the row of Table 16.

[0418] 1217. A TREM or TREM fragment according to any one of embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to the modified position in the row of Table 17.

[0419] 1218. A TREM or TREM fragment according to any of Embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to the modified position in the row of Table 18.

[0420] 1219. A TREM or TREM fragment according to any of Embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to the modified position in the row of Table 19.

[0421] 1220. A TREM or TREM fragment according to any one of embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to the modified position in the row of Table 20.

[0422] 1221. A TREM or TREM fragment according to any of Embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to the modified position in the row of Table 21.

[0423] 1222. A TREM or TREM fragment according to any one of embodiments 1001 to 1213, having a modified nucleotide at a position corresponding to the modified position in the row of Table 22.

[0424] 1223. A TREM or TREM fragment according to any of Embodiments 1001 to 1213, having a modified nucleotide at a first position and a modified nucleotide at a second position, wherein the first and second positions correspond to modified positions in any one row of Table 22.

[0425] 1224. A pharmaceutical composition comprising TREM or a TREM fragment of any of Embodiments 1000 to 1223.

[0426] 1225. The pharmaceutical composition according to Embodiment 1224, comprising pharmaceutically acceptable components, for example, excipients.

[0427] 1226. A lipid nanoparticle formulation comprising TREM or TREM fragments as described in any one of embodiments 1000 to 1213, or the pharmaceutical composition as described in claim 1224 or 1225.

[0428] 1227. A method for producing a TREM or TREM fragment according to any of Embodiments 1000 to 1213, comprising linking a first nucleotide to a second nucleotide to form a TREM or TREM fragment.

[0429] 1228. The method according to Embodiment 1227, wherein TREM or TREM fragments do not exist in nature (e.g., are synthetic).

[0430] 1229. The method according to Embodiment 1227, wherein the synthesis is performed in vitro.

[0431] 1230. The method according to Embodiment 1227, wherein TREM or TREM fragments are prepared by cell-free solid-phase synthesis.

[0432] 1231. Cells comprising TREM or TREM fragments as described in any of embodiments 1000 to 1213.

[0433] 1232. A method for regulating the intracellular tRNA pool, To provide a TREM or TREM fragment as described in any of embodiments 1000 to 1213, and The cells were brought into contact with TREM, A method that involves thereby regulating the intracellular tRNA pool.

[0434] 1233. A method for bringing cells, tissues, or subjects into contact with TREM or TREM fragments described in any of embodiments 1000 to 1213, Cells, tissues, or objects are brought into contact with TREM, A method comprising bringing cells, tissues, or objects into contact with TREM.

[0435] 1234. A method for providing TREM or TREM fragments to cells, tissues, or subjects, Cells, tissues, or subjects are brought into contact with TREM or TREM fragments described in any of Embodiments 1000 to 1213. A method comprising providing a TREM, a TREM core fragment, or a TREM fragment to cells, tissue, or a subject.

[0436] 1235. A method for forming cells, tissues, or objects that have come into contact with TREM, Cells, tissues, or subjects are brought into contact with TREM or TREM fragments described in any of Embodiments 1000 to 1213. A method comprising forming cells, tissues, or objects that have come into contact with TREM.

[0437] 1236. A method of using TREM, Cells, tissues, or subjects are brought into contact with TREM or TREM fragments described in any of Embodiments 1000 to 1213. This includes methods such as using TREM.

[0438] 1237. A method for applying TREM to cells, tissues, or subjects, Cells, tissues, or subjects are brought into contact with TREM or TREM fragments described in any of Embodiments 1000 to 1213. A method comprising applying TREM to cells, tissues, or subjects.

[0439] 1238. A method of exposing cells, tissues, or subjects to TREM, Cells, tissues, or subjects are brought into contact with TREM or TREM fragments described in any of Embodiments 1000 to 1213. A method comprising exposing cells, tissues, or subjects to TREM.

[0440] 1239. A method for forming TREM and a mixture of cells, tissues, or subjects, Cells, tissues, or subjects are brought into contact with TREM or TREM fragments described in any of Embodiments 1000 to 1213. A method comprising forming a mixture of TREM and cells, tissues, or the subject thereof.

[0441] 1240. A method for delivering TREM to cells, tissues, or subjects, A method comprising providing cells, tissues, or subjects, and contacting the cells, tissues, or subjects with a TREM or TREM fragment described in any of embodiments 1000 to 1213.

[0442] 1241. Methods for regulating metabolism, for example, the translational capacity of organelles, for example, ex vivo methods, A method comprising providing a preparation of an organelle, such as a mitochondria or chloroplast, and contacting the organelle with a TREM or TREM fragment described in any of embodiments 1000 to 1213.

[0443] 1242. A method for treating a subject, for example, by regulating metabolism in the subject, for example, by regulating the translational capacity of cells, The subject is provided with TREM or TREM fragments as described in any of embodiments 1000 to 1213, for example, administered, A method that includes treating the subject.

[0444] 1243. A method for regulating an intracellular tRNA pool comprising an endogenous open reading frame (ORF) containing 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 or TREM fragment described in any of Embodiments 1000 to 1213 in an amount sufficient to regulate the relative amounts of the first and second tRNA portions within the cell, and for a sufficient amount of time. This includes regulating the intracellular tRNA pool, Herein, TREM has a codon having a first sequence; or an anticodon that pairs with a codon other than the codon having the first sequence.

[0445] 1244. A method for regulating the tRNA pool in a subject having an endogenous open reading frame (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 the TREM or TREM fragment described in any of embodiments 1000 to 1213 in an amount and / or for a sufficient amount of time to adjust the relative amounts of the first tRNA portion and the second tRNA portion in the subject. This includes regulating the tRNA pool in the target, Herein, TREM has a codon having a first sequence; or an anticodon that pairs with a codon other than the codon having the first sequence.

[0446] 1245. A method for regulating the tRNA pool in a subject having an endogenous open reading frame (ORF) containing a codon containing a synonymous mutation (synonymous mutation codon or SMC), To provide a composition comprising a TREM or TREM fragment as described in any of Embodiments 1000 to 1213, wherein the TREM 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. A method that includes thereby regulating the tRNA pool in a target.

[0447] 1246. A method for regulating an intracellular tRNA pool containing an endogenous open reading frame (ORF) containing a codon containing a synonymous mutation (synonymous mutation codon or SMC), To provide a composition comprising a TREM or TREM fragment as described in any of Embodiments 1000 to 1213, wherein the TREM 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. A method that involves thereby regulating the intracellular tRNA pool.

[0448] 1247. A method for regulating the expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) containing a mutated codon, and the method is The cells are brought into contact with a composition comprising TREM or TREM fragment as described in any of Embodiments 1000 to 1213 in an amount sufficient to regulate the expression of the encoded protein and / or for a sufficient amount of time. This includes regulating the expression of proteins within cells. Herein, TREM has an anticodon that pairs with a codon having a mutation.

[0449] 1248. A method for regulating the expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) containing a mutated codon, and the method is The subject is brought into contact with a composition comprising TREM or TREM fragment as described in any of embodiments 1000 to 1213 in an amount sufficient to modulate the expression of the encoded protein and / or for a sufficient amount of time. This includes regulating protein expression in the target, Herein, TREM has an anticodon that pairs with a codon having a mutation.

[0450] 1249. The method according to Embodiment 1247 or 1248, wherein the mutation in ORF is a nonsense mutation resulting in an immature stop codon selected from, for example, UAA, UGA, or UAG.

[0451] The method according to embodiment 1247 or 1248, wherein 1250.TREM comprises an anticodon that pairs with a stop codon.

[0452] Other features, purposes, and advantages of the present invention will become apparent from the specification and claims.

[0453] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention pertains. All publications, patent applications, patents, and other references referenced herein are incorporated by reference as a whole. Furthermore, materials, methods, and examples are illustrative and not intended to be limiting.

[0454] Detailed description of a specific embodiment This disclosure features tRNA-based effector molecules (TREMs) including unnatural modifications and related methods. As disclosed herein, TREMs are complex molecules capable of mediating various cellular processes. Pharmaceutical TREM compositions, for example, TREMs containing unnatural modifications, may be administered to cells, tissues, or subjects to modulate these functions.

[0455] definition 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.

[0456] 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 Tables 5, 6, 7, 8, or 9.

[0457] When the term is used herein in relation to nucleotides, “unnatural modifications” refer to (a) modifications that cells, e.g., human cells, do not produce on endogenous tRNA; or (b) modifications that cells, e.g., human cells, may produce on endogenous tRNA, but such modifications are located at positions where they do not occur on endogenous tRNA, e.g., the modification is in a domain, linker or arm, or in a domain, linker or arm where such modification is not present in the nucleotide and / or in nature. In either case, the modifications are added by synthesis, e.g., in cell-free reactions, e.g., solid-phase or liquid-phase synthesis reactions. In some embodiments, unnatural modifications are modifications that do 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 Tables 5, 6, 7, 8, or 9.

[0458] 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.

[0459] 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.

[0460] When the term is used herein, “tRNA-based effector molecule” or “TREM” refers to an RNA molecule having the structure or properties of (a) to (v) below, which may be recombinant TREM, synthetic TREM, or TREM expressed from heterologous cells. 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. 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. TREMs may have several of the structures and functions of (a) to (v) (e.g., 2, 3, 4, 5, 6, 7, 8, 9).

[0461] In some embodiments, TREM is non-natural, as can be assessed by its structure or the method by which it is manufactured.

[0462] 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.)

[0463] 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 -R66 -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 -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 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.

[0464] In certain embodiments, the DHD is below the corresponding sequence of the consensus sequence provided in the "consensus sequence" interval or differs from the consensus sequence at one, two, five, or ten or fewer positions; In certain embodiments, the DHD is of 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 and ZZZ represents any of the 20 amino acids; In certain embodiments, the DHD is of Formula II 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 and ZZZ represents any of the 20 amino acids; In certain embodiments, the DHD is of Formula III ZZZ residue R 10 -R <{\rm{0000087}}>-R<{\rm{0000088}}>-R<{\rm{0000089}}>-R<{\rm{0000090}}>-R<{\rm{0000091}}>-R<{\rm{0000092}}>-R<{\rm{0000093}}>-R<{\rm{0000094}}>-R19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 including, where ZZZ represents any of the 20 amino acids; (b’) a residue R of the consensus sequence provided in the “consensus sequence” interval 29 a linker containing, for example, the linker 3 region; (c) an anticodon that binds to each codon in the mRNA, for example, an anticodon hairpin domain (ACHD) (the ACHD contains, for example, a sequence sufficient to mediate (with or without wobble) base pairing with the codon, such as an anticodon triplet, when present in other wild-type tRNAs; in certain embodiments, the ACHD has at least 75, 80, 85, 85, 90, 9, or 100% identity with a naturally occurring ACHD, such as the ACHD encoded by the nucleic acid in Table 1). In certain embodiments, TREM may include a fragment or analog of an ACHD, such as the ACHD encoded by the nucleic acid in Table 1, and the fragment in the embodiment has ACHD activity, while in other embodiments it does not have ACHD activity.

[0465] In certain embodiments, the ACHD is below the corresponding sequence of the consensus sequence provided in the “consensus sequence” interval or differs from the consensus sequence at 1, 2, 5, or 10 positions or less. In certain embodiments, the ACHD is of 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 -R44 -R 45 -R 46 It contains, and ZZZ represents one of the 20 amino acids; In one embodiment, ACHD is Equation II 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; 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, for example, an RNA sequence sufficient to act as a recognition site for an aminoacyl-tRNA synthetase for aminoacylation of TREM, for example, when present in other wild-type tRNAs, mediating recognition by the aminoacyl-tRNA synthetase). In embodiments, the VLD mediates stabilization of the tertiary structure of TREM. In certain embodiments, the VLD modulates, for example, increases, the specificity of TREM for its cognate amino acid, for example, the VLD modulates the cognate adapter function of TREM. In certain embodiments, the VLD has at least 75, 80, 85, 85, 90, 95, or 100% identity to a naturally occurring VLD, for example, the VLD encoded by the nucleic acid in Table 1. In certain embodiments, TREM may comprise a fragment or analog of a VLD, for example, the VLD encoded by the nucleic acid in Table 1, where the fragment in embodiments has VLD activity and in other embodiments does not have VLD activity.

[0466] In certain embodiments, the VLD is under the corresponding sequence of the consensus sequence provided in the "consensus sequence" interval.

[0467] In certain embodiments, the VLD is the residue - [R of the consensus sequence provided in the "consensus sequence" interval 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.

[0468] 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 -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 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 -R62 -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, e.g., its congener amino acids, and mediates the transfer of AA in polypeptide chain initiation or elongation; (i) Congeneral adapter function (TREM mediates the acceptance and incorporation of amino acids (e.g., congener amino acids) that are naturally bound to the anticodon of the TREM initiating or elongating 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.

[0469] In one embodiment, TREM comprises a full-length tRNA molecule or a fragment thereof.

[0470] In one embodiment, TREM includes the following characteristics: (a) to (e).

[0471] In one embodiment, TREM includes the following characteristics: (a) and (c).

[0472] In one embodiment, TREM includes the following characteristics: (a), (c), and (h).

[0473] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (b).

[0474] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (e).

[0475] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (b), and (e).

[0476] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (b), (e), and (g).

[0477] In one embodiment, TREM includes the following characteristics: (a), (c), (h), and (m).

[0478] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (g).

[0479] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (b).

[0480] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), and (e).

[0481] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), (g), (b), and (e).

[0482] In one embodiment, TREM includes the following characteristics: (a), (c), (h), (m), (g), (b), (e), and (q).

[0483] 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).

[0484] In one embodiment, the TREM includes a mobile RNA linker that provides the covalent bonds of (i) and (ii).

[0485] In one embodiment, TREM mediates protein translation.

[0486] 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.

[0487] 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].

[0488] 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.

[0489] 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.

[0490] In one embodiment, TREM is aminoacylated, for example, by loading amino acids with aminoacyl-tRNA synthetase.

[0491] In one embodiment, the TREM is unloaded with amino acids, for example, an unloaded TREM (uTREM).

[0492] 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).

[0493] 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.

[0494] 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].

[0495] 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.

[0496] 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.

[0497] 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.

[0498] "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).

[0499] 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.

[0500] 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.

[0501] 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.

[0502] "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).

[0503] "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.

[0504] 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.

[0505] "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.

[0506] "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.

[0507] 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.

[0508] When the term "tRNA" is used herein, it refers to transtransition ribonucleic acid that is naturally present in its natural state.

[0509] 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).

[0510] 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.

[0511] 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.

[0512] In one embodiment, at least X% of the TREM in the TREM composition has a non-natural modification at the first position, and less than Y% has a non-natural modification at the second position, where X is 80, 90, 95, 96, 97, 98, 99, or 99.5, and Y is 20, 20, 5, 2, 1, .1, or .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.

[0513] TREM, TREM core fragments, and TREM fragments "tRNA-based effector molecule" or "TREM" refers to an RNA molecule containing one or more of the properties described herein. TREMs may include, for example, unnatural modifications as provided in Tables 4, 5, 6, or 7.

[0514] 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.

[0515] 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.

[0516] 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).

[0517] 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.

[0518] 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.

[0519] 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.

[0520] [Table 1]

[0521] [Table 2]

[0522] [Table 3]

[0523] In one embodiment, TREM includes a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence disclosed in Table 1, for example, one of sequence numbers 1 to 451 disclosed in Table 1. In another embodiment, 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 sequence numbers 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.

[0524] 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.

[0525] 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.

[0526] 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.

[0527] 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.

[0528] [Table 4]

[0529] Table 5

[0530] Table 6

[0531] Table 7

[0532] Table 8

[0533] Table 9

[0534] Table 10

[0535] Table 11

[0536] Table 12

[0537] Table 13

[0538] Table 14

[0539] Table 15

[0540] Table 16

[0541] Table 17

[0542] Table 18

[0543] Table 19

[0544] Table 20

[0545] Table 21

[0546] Table 22

[0547] Table 23

[0548] Table 24

[0549] Table 25

[0550] non-natural modification The TREMs, TREM core fragments, or TREM fragments described herein include unnatural modifications, such as those listed in any one of Tables 5 to 9. These unnatural modifications may be prepared according to methods known in the art. Exemplary methods for preparing unnatural modifications are provided in Examples 4 to 7.

[0551] In one embodiment, a non-native modification is a modification that cells, such as human cells, do not produce on endogenous tRNA.

[0552] 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.

[0553] In some embodiments, the TREM, TREM core fragment, or TREM fragment described herein includes unnatural modifications provided in Table 5, or combinations thereof.

[0554] [Table 26]

[0555] [Table 27]

[0556] [Table 28]

[0557] [Table 29]

[0558] [Table 30]

[0559] [Table 31]

[0560] [Table 32]

[0561] [Table 33]

[0562] [Table 34]

[0563] [Table 35]

[0564] In some embodiments, the TREM, TREM core fragment, or TREM fragment described herein includes modifications, or combinations thereof, provided in Table 6. The modifications provided in Table 6 are used on synthetic TREM, TREM core fragment, or TREM fragment at positions that are naturally present in RNA and, as used herein, not naturally occurring.

[0565] [Table 36]

[0566] [Table 37]

[0567] [Table 38]

[0568] In some embodiments, the TREM, TREM core fragment, or TREM fragment described herein includes unnatural modifications or combinations thereof provided in Table 7.

[0569] [Table 39]

[0570] [Table 40]

[0571] [Table 41]

[0572] In some embodiments, the TREM, TREM core fragment, or TREM fragment described herein includes unnatural modifications provided in Table 8, or combinations thereof.

[0573] [Table 42]

[0574] [Table 43]

[0575] In some embodiments, the TREM, TREM core fragment, or TREM fragment described herein includes unnatural modifications provided in Table 9, or combinations thereof.

[0576] [Table 44]

[0577] 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.

[0578] TREM Consensus Array In one embodiment, the TREM disclosed herein includes a consensus sequence provided herein.

[0579] 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.)

[0580] 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).

[0581] 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).

[0582] 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.

[0583] 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 29Does 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 -R 60 -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 includes properties selected from those that form a linker region, for example, a linker 4 region.

[0584] 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 , R 25 , 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 , R60 , 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.

[0585] 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.

[0586] 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 , R64 = 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 , R20 , 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.

[0587] 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 -R68 -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 , R 12 , 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.

[0588] In one embodiment, the TREM disclosed herein is Equation II ARG (Sequence number 566) array, 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 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 , R50 = 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.

[0589] In one embodiment, the TREM disclosed herein is of Formula III ARG (SEQ ID NO: 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 , R 44 = 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 , R 52 , 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.

[0590] 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 -R20 -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 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; R 40 , 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.

[0591] 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 -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 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 , R 49 , 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.

[0592] 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 -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 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, R 13 , 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.

[0593] 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; R50 , 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 , R 59 , 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.

[0594] 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 -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 = 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, R 11 , 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.

[0595] 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 -R68 -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 , R49 , 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 , 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.

[0596] 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 , R 50 = Independently C, G, U, or non-existent; R 11 , R 22 , R 23 , R 35 , R 36 , R59 , 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.

[0597] 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 -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 39 , R 41 , R 45 , R 57 = 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 , R28 , 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 , R 21 , 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.

[0598] 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 -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 34 , R 39 , R 41 , R45 , 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 , R 72 = 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 , R32 , 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.

[0599] 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 , R 27 , 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 , R 20 = 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.

[0600] 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 -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 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 , R 64 = 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.

[0601] In one embodiment, the TREM disclosed herein is Equation III GLNThe array of (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 , R 71 = 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 , R 20 = 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.

[0602] 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 -R20 -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 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, R12 , 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 , R 57 = 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 , R60 = 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.

[0603] 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 -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 Glu is, R0, R 18 , R 23 = non-existent, R 17 , R 40 = Independently A or non-existent; R 26 , R 27 , R 34 , R 43 , 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 = Independently A, C, U, or non-existent; R9, R 14 , R 24 , R 25 , R 52 , R 56 , R 63 = Independently A, G, or non-existent; R7, R 15 , R 46 , R 50 , R 67 , R 72 = Independently A, G, U, or non-existent; R 29 , R 57 = Independently A, U, or non-existent; R 60 = C or non-existent; R 39 = C, G, or non-existent; R3, R6, R 20 , R 30 , R 32 , R 42 , R55 , R 62 , R 65 = Independently C, G, U, or non-existent; R4, R8, R 16 , R 28 , R 35 , R 37 , R 49 , R 53 , R 59 = Independently C, U, or non-existent; R 10 , R 19 = Independently G or non-existent; R 22 , R 64 = Independently G, U, or non-existent; R 11 , R 13 , 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.

[0604] In one embodiment, the TREM disclosed herein is Equation III GLU The array (sequence number 582), 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 Glu is, R0, R 17 , R 18 , R 23 = non-existent, R 14 , R 27 , R 40 , R 71 = Independently A or non-existent; R44 = A, C, or non-existent; R 43 = A, C, G or non-existent; R1, R 31 , R 33 , R 45 , R 51 , R 66 = Independently N or non-existent; R 21 , R 41 = Independently A, C, U, or non-existent; R7, R 24 , R 25 , R 50 , R 52 , R 56 , R 63 , R 68 , R 70 = Independently A, G, or non-existent; R5, R 46 = Independently A, G, U, or non-existent; R 29 , R 57 , R 67 , R 72 = Independently A, U, or non-existent; R2, R 39 , R 60 = Independently C or non-existent; R3, R 12 , R 20 , R 26 , R 34 , R 69 = Independently C, G, or non-existent; R6, R 30 , R 42 , R 48 , R 65 = Independently C, G, U, or non-existent; R4, R 16 , R 28 , R 35 , R 37 , R 49 , R 53 , R 55 , R 58 , R 61 , R 62 = Independently C, U, or non-existent; R9, R 10 , R19 , R 64 = Independently G or non-existent; R 15 , R 22 , R 32 = Independently G, U, or non-existent; R8, R 11 , R 13 , R 36 , R 38 , 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.

[0605] Glycine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I GLY The array (sequence number 583), 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 is 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a bonucleotide residue, and the consensus regarding Gly is, R0 = non-existence; R 24 = A or non-existent; R3, R9, R 40 , R 50 , R 51 = Independently A, C, G, or non-existent; R4, R5, R6, R7, R 12 , R 16 , R 21 , R 22 , R 26 , R 29 , R 30 , R 31 , R 32 , R 34 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 58 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 = Independently N or non-existent; R 59 = A, C, U, or non-existent; R1, R 10 , R 14 , R 15 , R 27 , R 56 = Independently A, G, or non-existent; R 20 , R 25 = Independently A, G, U, or non-existent; R 57 , R 72 = Independently A, U, or non-existent; R38 , R 39 , R 60 = Independently C or non-existent; R 52 = C, G, or non-existent; R2, R 19 , R 37 , R 54 , R 55 , R 61 , R 62 , R 69 , R 70 = Independently C, G, U, or non-existent; R 11 , R 13 , R 17 , R 28 , R 35 , R 36 , R 71 = Independently C, U, or non-existent; R8, R 18 , R 23 , 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.

[0606] In one embodiment, the TREM disclosed herein is Equation II GLY Includes the array (sequence number 584), 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 Gly is, R0, R 18 , R 23 = non-existent, R 24 , R 27 , R 40 , R 72 = Independently A or non-existent; R 26= A, C, or non-existent; R3, R7, R 68 = Independently A, C, G, or non-existent; R5, R 30 , R 41 , R 42 , R 44 , R 49 , R 67 = Independently A, C, G, U or non-existent; R 31 , R 32 , R 34 = Independently A, C, U, or non-existent; R9, R 10 , R 14 , R 15 , R 33 , R 50 , R 56 = Independently A, G, or non-existent; R 12 , R 16 , R 22 , R 25 , R 29 , R 46 = Independently A, G, U, or non-existent; R 57 = A, U, or non-existent; R 17 , R 38 , R 39 , R 60 , R 61 , R 71 = Independently C or non-existent; R6, R 52 , R 64 , R 66 = Independently C, G, or non-existent; R2, R4, R 37 , R 48 , R 55 , R 65 = Independently C, G, U or non-existent; R 13 , R 35 , R 43 , R 62 , R 69 = Independently C, U, or non-existent; R1, R 19 , R 20 , R 51 , R70 = Independently G or non-existent; R 21 , R 45 , R 63 = Independently G, U, or non-existent; R8, R 11 , R 28 , R 36 , R 53 , R 54 , R 58 , 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.

[0607] In one embodiment, the TREM disclosed herein is Equation III GLY The array (sequence number 585), 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 Gly is, R0, R 18 , R 23 = non-existent, R 24 , R 27 , R 40 , R 72 = Independently A or non-existent; R 26 = A, C, or non-existent; R3, R7, R 49 , R 68 = Independently A, C, G, or non-existent; R5, R 30 , R 41 , R 44 , R 67 = Independently N or non-existent; R 31 , R 32 , R 34 = Independently A, C, U, or non-existent; R9, R 10 , R 14 , R 15 , R 33 , R 50 , R 56 = Independently A, G, or non-existent; R 12 , R 25 , R 29 , R 42 , R 46 = Independently A, G, U, or non-existent; R 16 , R 57 = Independently A, U, or non-existent; R 17 , R 38 , R 39 , R 60 , R 61 , R 71 = Independently C or non-existent; R6, R 52 , R 64 , R66 = Independently C, G, or non-existent; R 37 , R 48 , R 65 = Independently C, G, U, or non-existent; R2, R4, R 13 , R 35 , R 43 , R 55 , R 62 , R 69 = Independently C, U, or non-existent; R1, R 19 , R 20 , R 51 , R 70 = Independently G or non-existent; R 21 , R 22 , R 45 , R 63 = Independently G, U, or non-existent; R8, R 11 , R 28 , R 36 , R 53 , R 54 , R 58 , 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.

[0608] Histidine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I HIS Sequence of (Sequence No. 586), 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 His is, R 23 = non-existent; R 14 , R 24 , R 57 = Independently A or non-existent; R 72 = A, C, or non-existent; R9, R 27 , R 43 , R 48 , R 69 = Independently A, C, G, or non-existent; R3, R4, R5, R6, R 12 , R 25 , R 26 , R 29 , R 30 , R 31 , R 34 , R 42 , R 45 , R 46 , R 49 , R 50 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 = Independently N or non-existent; R 13 , R 21 , R 41 , R 44 , R 65 = Independently A, C, U, or non-existent; R 40 , R 51 , R 56 , R 70 = Independently A, G, or non-existent; R7, R 32 = Independently A, G, U, or non-existent; R 55 , R 60 = Independently C or non-existent; R 11 , R 16 , R 33 , R 64 = Independently C, G, U, or non-existent; R2, R 17 , R 22 , R 28 , R 35 , R 53 , R 59 , R 61 , R 71 = Independently C, U, or non-existent; R1, R 10 , R 15 , R19 , R 20 , R 37 , R 39 , R 52 = Independently G or non-existent; R0 = G, U, or non-existence; R8, R 18 , 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.

[0609] In one embodiment, the TREM disclosed herein is Equation II HIS The array (sequence number 587), 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 His is, R0, R 17 , R 18 , R 23 = non-existent; R7, R 12 , R 14 , R 24 , R 27 , R 45 , R 57 , R 58 , R 63 , R 67 , R 72 = Independently A or non-existent; R3 = A, C, U, or non-existent; R4, R 43 , R 56 , R 70 = Independently A, G, or non-existent; R 49 = A, U, or non-existent; R2, R 28 , R 30 , R 41 , R 42 , R 44 , R 48 , R 55 , R 60 , R 66 , R 71 = Independently C or non-existent; R 25 = C, G, or non-existent; R9 = C, G, U, or non-existent; R8, R 13 , R 26 , R 33 , R 35 , R 50 , R 53 , R 61 , R 68 = Independently C, U, or non-existent; R1, R6, R 10 , R 15 , R 19 , R 20 , R 32 , R34 , R 37 , R 39 , R 40 , R 46 , R 51 , R 52 , R 62 , R 64 , R 69 = Independently G or non-existent; R 16 = G, U, or non-existent; R5, R 11 , R 21 , R 22 , R 29 , R 31 , R 36 , R 38 , 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.

[0610] In one embodiment, the TREM disclosed herein is Equation III HIS The array (sequence number 588), 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 His is, R0, R 17 , R 18 , R 23 = non-existent; R7, R 12 , R 14 , R 24 , R 27 , R 45 , R 57, R 58 , R 63 , R 67 , R 72 = Independently A or non-existent; R3 = A, C, or non-existence; R4, R 43 , R 56 , R 70 = Independently A, G, or non-existent; R 49 = A, U, or non-existent; R2, R 28 , R 30 , R 41 , R 42 , R 44 , R 48 , R 55 , R 60 , R 66 , R 71 = Independently C or non-existent; R8, R9, R 26 , R 33 , R 35 , R 50 , R 61 , R 68 = Independently C, U, or non-existent; R1, R6, R 10 , R 15 , R 19 , R 20 , R 25 , R 32 , R 34 , R 37 , R 39 , R 40 , R 46 , R 51 , R 52 , R 62 , R 64 , R 69 = Independently G or non-existent; R5, R 11 , R 13 , R 16 , R 21 , R 22 , R 29 , R 31 , R 36 , R 38 , R 53 , R 54 , R 59 , R65 = 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.

[0611] Isoleucine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I ILE The array (sequence number 589), 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 Ile is, R 23 = non-existent; R38 , R 41 , R 57 , R 72 = Independently A or non-existent; R1, R 26 = Independently A, C, G, or non-existent; R0, R3, R4, R6, R 16 , R 31 , R 32 , R 34 , R 37 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 59 , R 62 , R 63 , R 64 , R 66 , R 67 , R 68 , R 69 = Independently N or non-existent; R 22 , R 61 , R 65 = Independently A, C, U, or non-existent; R9, R 14 , R 15 , R 24 , R 27 , R 40 = Independently A, G, or non-existent; R7, R 25 , R 29 , R 51 , R 56 = Independently A, G, U, or non-existent; R 18 , R 54 = Independently A, U, or non-existent; R 60 = C or non-existent; R2, R 52 , R 70 = Independently C, G, or non-existent; R5, R 12 , R 21 , R 30 , R 33, R 71 = Independently C, G, U, or non-existent; R 11 , R 13 , R 17 , R 28 , R 35 , R 53 , R 55 = Independently C, U, or non-existent; R 10 , R 19 , R 20 = Independently G or non-existent; R8, R 36 , R 39 = 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.

[0612] In one embodiment, the TREM disclosed herein is Equation II ILE (Array of sequence number 590) 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 -R62 -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 Ile is, R0, R 18 , R 23 = non-existent, R 24 , R 38 , R 40 , R 41 , R 57 , R 72 = Independently A or non-existent; R 26 , R 65 = Independently A, C, or non-existent; R 58 , R 59 , R 67 = Independently N or non-existent; R 22 = A, C, U, or non-existent; R6, R9, R 14 , R 15 , R 29 , R 34 , R 43 , R 46 , R 48 , R 50 , R 51 , R 63 , R 69 = Independently A, G, or non-existent; R 37 , R 56 = Independently A, G, U, or non-existent; R 54 = A, U, or non-existent; R 28 , R 35 , R 60 , R 62 , R 71 = Independently C or non-existent; R2, R 52 , R 70= Independently C, G, or non-existent; R5 = C, G, U, or non-existent; R3, R4, R 11 , R 13 , R 17 , R 21 , R 30 , R 42 , R 44 , R 45 , R 49 , R 53 , R 55 , R 61 , R 64 , R 66 = Independently C, U, or non-existent; R1, R 10 , R 19 , R 20 , R 25 , R 27 , R 31 , R 68 = Independently G or non-existent; R7, R 12 , R 32 = Independently G, U, or non-existent; R8, R 16 , R 33 , R 36 , R 39 = 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.

[0613] In one embodiment, the TREM disclosed herein is Equation III ILE The array (sequence number 591), 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 Ile is, R0, R 18 , R 23 = non-existent, R 14 , R 24 , R 38 , R 40 , R 41 , R 57 , R 72 = Independently A or non-existent; R 26 , R 65 = Independently A, C, or non-existent; R 22 , R 59 = Independently A, C, U, or non-existent; R6, R9, R 15 , R 34 , R 43 , R 46 , R 51 , R 56 , R 63 , R 69 = Independently A, G, or non-existent; R 37 = A, G, U, or non-existent; R 13 , R 28 , R 35 , R 44 , R 55 , R 60 , R 62 , R 71 = Independently C or non-existent; R2, R5, R 70 = Independently C, G, or non-existent; R 58 , R 67 = Independently C, G, U, or non-existent; R3, R4, R 11 , R 17 , R 21 , R 30 , R 42 , R 45 , R 49 , R 53 , R 61 , R 64 , R 66 = Independently C, U, or non-existent; R1, R 10 , R 19 , R 20 , R 25 , R 27 , R 29 , R 31 , R 32 , R 48 , R 50 , R 52 , R 68 = Independently G or non-existent; R7, R12 = Independently G, U, or non-existent; R8, R 16 , R 33 , R 36 , R 39 , 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.

[0614] Methionine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I METThe array of (array number 592), 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[[ID=4३]] 30 -R 31 -R 32 [[ID=४८]]-R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R[[ID=7१]] 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<00०4231>-R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 It should be noted that there seems to be an error in the original text where "४८" and "०००४२३१" are present. I have translated them as they are but they might be incorrect in the original context.-R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Met is, R0, R 23 = non-existent; R 14 , R 38 , R 40 , R 57 = Independently A or non-existent; R 60 = A, C, or non-existent; R 33 , R 48 , R 70 = Independently A, C, G, or non-existent; R1, R3, R4, R5, R6, R 11 , R 12 , R 16 , R 17 , R 21 , R 22 , R 26 , R 27 , R 29 , R 30 , R 31 , R 32 , R 42 , R 44 , R 45 , R 46 , R 49 , R 50 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 , R 69 , R 71 = Independently N or non-existent; R 18 , R 35 , R 41 , R 59 , R 65 = Independently A, C, U, or non-existent; R9, R 15 , R 51 = Independently A, G, or non-existent; R7, R 24 , R 25 , R 34 , R 53 , R 56 = Independently A, G, U, or non-existent; R 72 = A, U, or non-existent; R 37 = C or non-existent; R 10 , R 55 = Independently C, G, or non-existent; R2, R 13 , R 28 , R 43 , R 64 = Independently C, G, U, or non-existent; R 36 , R 61 = Independently C, U, or non-existent; R 19 , R 20 , R 52 = Independently G or non-existent; R8, R 39 , 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.

[0615] In one embodiment, the TREM disclosed herein is Equation II MET Includes the sequence (sequence number 593), 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 Met is, R0, R 18 , R 22 , R 23 = non-existent, R 14 , R 24 , R 38 , R 40 , R 41 , R 57 , R 72= Independently A or non-existent; R 59 , R 60 , R 62 , R 65 = Independently A, C, or non-existent; R6, R 45 , R 67 = Independently A, C, G, or non-existent; R4 = N or does not exist; R 21 , R 42 = Independently A, C, U, or non-existent; R1, R9, R 27 , R 29 , R 32 , R 46 , R 51 = Independently A, G, or non-existent; R 17 , R 49 , R 53 , R 56 , R 58 = Independently A, G, U, or non-existent; R 63 = A, U, or non-existent; R3, R 13 , R 37 = Independently C or non-existent; R 48 , R 55 , R 64 , R 70 = Independently C, G, or non-existent; R2, R5, R 66 , R 68 = Independently C, G, U, or non-existent; R 11 , R 16 , R 26 , R 28 , R 30 , R 31 , R 35 , R 36 , R 43 , R 44 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 12 , R 15 , R19 , R 20 , R 25 , R 33 , R 52 , R 69 = Independently G or non-existent; R7, R 34 , R 50 = Independently G, U, or non-existent; R8, R 39 , 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.

[0616] In one embodiment, the TREM disclosed herein is Equation III MET The array (sequence number 594), 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 -R68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Met is, R0, R 18 , R 22 , R 23 = non-existent, R 14 , R 24 , R 38 , R 40 , R 41 , R 57 , R 72 = Independently A or non-existent; R 59 , R 62 , R 65 = Independently A, C, or non-existent; R6, R 67 = Independently A, C, G, or non-existent; R4, R 21 = Independently A, C, U, or non-existent; R1, R9, R 27 , R 29 , R 32 , R 45 , R 46 , R 51 = Independently A, G, or non-existent; R 17 , R 56 , R 58 = Independently A, G, U, or non-existent; R 49 , R 53 , R 63 = Independently A, U, or non-existent; R3, R 13 , R 26 , R 37 , R 43 , R 60 = Independently C or non-existent; R2, R 48 , R 55 , R 64 , R 70 = Independently C, G, or non-existent; R5, R 66= Independently C, G, U, or non-existent; R 11 , R 16 , R 28 , R 30 , R 31 , R 35 , R 36 , R 42 , R 44 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 12 , R 15 , R 19 , R 20 , R 25 , R 33 , R 52 , R 69 = Independently G or non-existent; R7, R 34 , R 50 , R 68 = Independently G, U, or non-existent; R8, R 39 , 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.

[0617] Leucine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I LEU The array (sequence number 595), 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 -R20 -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 Leu is, R0 = non-existence; R 38 , R 57 = Independently A or non-existent; R 60 = A, C, or non-existent; R1, R13 , R 27 , R 48 , R 51 , R 56 = Independently A, C, G, or non-existent; R2, R3, R4, R5, R6, R7, R9, R 10 , R 11 , R 12 , R 16 , R 23 , R 26 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 37 , R 41 , R 42 , R 43 , 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 69 , R 70 = Independently N or non-existent; R 17 , R 18 , R 21 , R 22 , R 25 , R 35 , R 55 = Independently A, C, U, or non-existent; R 14 , R 15 , R 39 , R 72 = Independently A, G, or non-existent; R 24 , R 40 = Independently A, G, U, or non-existent; R 52 , R 61 , R 64 , R 71 = Independently C, G, U, or non-existent; R36 , R 53 , R 59 = Independently C, U, or non-existent; R 19 =G or non-existent; R 20 = G, U, or non-existent; R8, 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.

[0618] In one embodiment, the TREM disclosed herein is Equation IILEU (Array No. 596)'s array, 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<000475​​​​​​​71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Leu is, R0 = non-existence, R 38 , R 57 , R 72 = Independently A or non-existent; R 60 = A, C, or non-existent; R4, R5, R 48 , R 50 , R 56 , R 69 = Independently A, C, G or non-existent; R6, R 33 , R 41 , R 43 , R 46 , R 49 , R 58 , R 63 , R 66 , R 70 = Independently N or non-existent; R 11 , R 12 , R 17 , R 21 , R 22 , R 28 , R 31 , R 37 , R 44 , R 55 = Independently A, C, U, or non-existent; R1, R9, R 14 , R 15 , R 24 , R 27 , R 34 , R 39 = Independently A, G, or non-existent; R7, R 29 , R 32 , R 40 , R 45 = Independently A, G, U, or non-existent; R 25 = A, U, or non-existent; R 13 = C, G, or non-existent; R2, R3, R 16 , R 26 , R 30, R 52 , R 62 , R 64 , R 65 , R 67 , R 68 = Independently C, G, U, or non-existent; R 18 , R 35 , R 42 , R 53 , R 59 , R 61 , R 71 = Independently C, U, or non-existent; R 19 , R 51 = Independently G or non-existent; R 10 , R 20 = Independently G, U, or non-existent; R8, R 23 , R 36 , 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.

[0619] In one embodiment, the TREM disclosed herein is Equation III LEU The array (sequence number 597), 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 Leu is, R0 = non-existence, R 38 , R 57 , R 72 = Independently A or non-existent; R 60 = A, C, or non-existent; R4, R5, R 48 , R50 , R 56 , R 58 , R 69 = Independently A, C, G, or non-existent; R6, R 33 , R 43 , R 46 , R 49 , R 63 , R 66 , R 70 = Independently N or non-existent; R 11 , R 12 , R 17 , R 21 , R 22 , R 28 , R 31 , R 37 , R 41 , R 44 , R 55 = Independently A, C, U, or non-existent; R1, R9, R 14 , R 15 , R 24 , R 27 , R 34 , R 39 = Independently A, G, or non-existent; R7, R 29 , R 32 , R 40 , R 45 = Independently A, G, U, or non-existent; R 25 = A, U, or non-existent; R 13 = C, G, or non-existent; R2, R3, R 16 , R 30 , R 52 , R 62 , R 64 , R 67 , R 68 = Independently C, G, U, or non-existent; R 18 , R 35 , R 42 , R 53 , R 59 , R 61 , R 65 , R 71 = Independently C, U, or non-existent; R 19 , R 51 = Independently G or non-existent; R 10 , R 20 , R 26 = Independently G, U, or non-existent; R8, R 23 , R 36 , 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.

[0620] Lysine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I LYS Includes the sequence (sequence number 598), 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 Lys is, R0 = non-existence, R 14 = A or non-existent; R 40 , R 41 = Independently A, C, or non-existent; R 34 , R 43 , R 51 = Independently A, C, G, or non-existent; R1, R2, R3, R4, R5, R6, R7, R 11 , R 12 , R 16 , R 21 , R 26 , R 30 , R 31 , R 32 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 62 , R 63 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 13 , R 17 , R 59 , R 71 = Independently A, C, U, or non-existent; R9, R 15 , R 19 , R 20 , R 25 , R 27 , R 52 , R 56 = Independently A, G, or non-existent; R 24 , R 29 , R72 = Independently A, G, U, or non-existent; R 18 , R 57 = Independently A, U, or non-existent; R 10 , R 33 = Independently C, G, or non-existent; R 42 , R 61 , R 64 = Independently C, G, U, or non-existent; R 28 , R 35 , R 36 , R 37 , R 53 , R 55 , R 60 = Independently C, U, or non-existent; R8, R 22 , R 23 , R 38 , R 39 , 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.

[0621] In one embodiment, the TREM disclosed herein is Equation II LYS Includes the array (sequence number 599), 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 Lys is, R0, R 18 , R 23 = non-existent, R 14 = A or non-existent; R 40 , R 41 , R 43 = Independently A, C, or non-existent; R3, R7 = independently A, C, G, or non-existence; R1, R6, R 11 , R 31 , R 45 , R 48 , R 49 , R 63 , R 65 , R 66 , R 68 = Independently N or non-existent; R2, R 12 , R 13 , R 17 , R 44 , R 67 , R 71 = Independently A, C, U, or non-existent; R9, R 15 , R 19 , R 20 , R 25 , R 27 , R 34 , R 50 , R 52 , R 56 , R 70 , R 72 = Independently A, G, or non-existent; R5, R 24 , R 26 , R 29 , R 32 , R 46 , R 69 = Independently A, G, U, or non-existent; R 57 = A, U, or non-existent; R 10 , R 61 = Independently C, G, or non-existent; R4, R 16 , R 21 , R 30 , R 58 , R 64 = Independently C, G, U, or non-existent; R 28 , R 35 , R 36 , R 37 , R 42 , R 53 , R 55 , R 59 , R 60, R 62 = Independently C, U, or non-existent; R 33 , R 51 = Independently G or non-existent; R8 = G, U, or non-existence; R 22 , R 38 , R 39 , 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.

[0622] In one embodiment, the TREM disclosed herein is Equation III LYS Includes the sequence (sequence number 600), 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 Lys is, R0, R 18 , R 23 = non-existent, R9, R 14 , R 34 , R 41 = Independently A or non-existent; R 40 = A, C, or non-existent; R1, R3, R7, R 31 = Independently A, C, G, or non-existent; R 48 , R 65 , R 68 = Independently N or non-existent; R2, R 13 , R 17 , R 44 , R 63 , R 66 = Independently A, C, U, or non-existent; R5, R 15 , R 19 , R 20 , R 25 , R 27 , R 29 , R 50 , R 52 , R 56 , R 70 , R 72 = Independently A, G, or non-existent; R6, R 24 , R 32 , R 49 = Independently A, G, U, or non-existent; R 12 , R 26 , R 46 , R 57 = Independently A, U, or non-existent; R 11 , R 28 , R 35 , R 43 = Independently C or non-existent; R 10 , R45 , R 61 = Independently C, G, or non-existent; R4, R 21 , R 64 = Independently C, G, U, or non-existent; R 37 , R 53 , R 55 , R 59 , R 60 , R 62 , R 67 , R 71 = Independently C, U, or non-existent; R 33 , R 51 = Independently G or non-existent; R8, R 30 , R 58 , R 69 = Independently G, U, or non-existent; R 16 , R 22 , R 36 , R 38 , R 39 , R 42 , 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.

[0623] Phenylalanine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I PHE The sequence (sequence number 601), 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 Phe is, R0, R 23 = non-existent; R9, R 14 , R 38 , R 39 , R 57 , R 72 = Independently A or non-existent; R71 = A, C, or non-existent; R 41 , R 70 = Independently A, C, G, or non-existent; R4, R5, R6, R 30 , R 31 , R 32 , R 34 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 58 , R 62 , R 63 , R 66 , R 67 , R 68 , R 69 = Independently N or non-existent; R 16 , R 61 , R 65 = Independently A, C, U, or non-existent; R 15 , R 26 , R 27 , R 29 , R 40 , R 56 = Independently A, G or non-existent; R7, R 51 = Independently A, G, U, or non-existent; R 22 , R 24 = Independently A, U, or non-existent; R 55 , R 60 = Independently C or non-existent; R2, R3, R 21 , R 33 , R 43 , R 50 , R 64 = Independently C, G, U, or non-existent; R 11 , R 12 , R 13 , R 17 , R 28 , R 35 , R 36 , R 59 = Independently C, U, or non-existent; R10 , R 19 , R 20 , R 25 , R 37 , R 52 = Independently G or non-existent; R1 = G, U, or non-existent; R8, R 18 , 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.

[0624] In one embodiment, the TREM disclosed herein is Equation II PHE The sequence (sequence number 602), 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 -R70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Phe is, R0, R 18 , R 23 = non-existent; R 14 , R 24 , R 38 , R 39 , R 57 , R 72 = Independently A or non-existent; R 46 , R 71 = Independently A, C, or non-existent; R4, R 70 = Independently A, C, G, or non-existent; R 45 = A, C, U, or non-existent; R6, R7, R 15 , R 26 , R 27 , R 32 , R 34 , R 40 , R 41 , R 56 , R 69 = Independently A, G, or non-existent; R 29 = A, G, U, or non-existent; R5, R9, R 67 = Independently A, U, or non-existent; R 35 , R 49 , R 55 , R 60 = Independently C or non-existent; R 21 , R 43 , R 62 = Independently C, G, or non-existent; R2, R 33 , R 68 = Independently C, G, U, or non-existent; R3, R 11 , R 12 , R 13 , R 28 , R 30 , R 36, R 42 , R 44 , R 48 , R 58 , R 59 , R 61 , R 66 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 25 , R 37 , R 51 , R 52 , R 63 , R 64 = Independently G or non-existent; R1, R 31 , R 50 = Independently G, U, or non-existent; R8, R 16 , R 17 , R 22 , R 53 , R 54 , 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.

[0625] In one embodiment, the TREM disclosed herein is Equation III PHE The sequence (sequence number 603), 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 Phe is, R0, R 18 , R 22 , R 23 = non-existent; R5, R7, R 14 , R 24 , R 26 , R 32 , R 34 , R 38 , R39 , R 41 , R 57 , R 72 = Independently A or non-existent; R 46 = A, C, or non-existent; R 70 = A, C, G or non-existent; R4, R6, R 15 , R 56 , R 69 = Independently A, G, or non-existent; R9, R 45 = Independently A, U, or non-existent; R2, R 11 , R 13 , R 35 , R 43 , R 49 , R 55 , R 60 , R 68 , R 71 = Independently C or non-existent; R 33 = C, G, or non-existent; R3, R 28 , R 36 , R 48 , R 58 , R 59 , R 61 = Independently C, U, or non-existent; R1, R 10 , R 19 , R 20 , R 21 , R 25 , R 27 , R 29 , R 37 , R 40 , R 51 , R 52 , R 63 , R 64 = Independently G or non-existent; R8, R 12 , R 16 , R 17 , R 30 , R 31 , R 42 , R 44 , R 50 , R 53 , R 54 , R65 , R 66 , R 67 = 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.

[0626] Proline TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I PRO The array (sequence number 604), R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R12 -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 Pro is, R0 = non-existence R 14 , R 57 = Independently A or non-existent; R 70 , R 72 = Independently A, C, or non-existent; R9, R 26 , R 27 = Independently A, C, G, or non-existent; R4, R5, R6, R 16 , R 21 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 37 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 61 , R 62 , R 63 , R 64 , R 66 , R 67 , R 68 = Independently N or non-existent; R 35 , R 65 = Independently A, C, U, or non-existent; R 24 , R 40 , R 56 = Independently A, G, or non-existent; R7, R 25 , R 51 = Independently A, G, U, or non-existent; R 55 , R 60 = Independently C or non-existent; R1, R3, R 71 = Independently C, G, or non-existent; R 11 , R 12 , R 20 , R 69 = Independently C, G, U, or non-existent; R 13 , R 17 , R 18 , R 22 , R 23 , R 28 , R 59 = Independently C, U, or non-existent; R 10 , R 15 , R 19 , R 38 , R 39 , R 52 , = independently G or non-existent; R2 = independently G, U, or non-existent; R8, 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.

[0627] In one embodiment, the TREM disclosed herein is Equation II PRO The array (sequence number 605), 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 Pro is, R0, R 17 , R 18 , R 22 , R 23 = non-existent; R 14 , R 45 , R 56 , R 57 , R 58 , R65 , R 68 = Independently A or non-existent; R 61 = A, C, G or non-existent; R 43 =N or nonexistent; R 37 = A, C, U, or non-existent; R 24 , R 27 , R 33 , R 40 , R 44 , R 63 = Independently A, G or non-existent; R3, R 12 , R 30 , R 32 , R 48 , R 55 , R 60 , R 70 , R 71 , R 72 = Independently C or non-existent; R5, R 34 , R 42 , R 66 = Independently C, G, or non-existent; R 20 = C, G, U, or non-existent; R 35 , R 41 , R 49 , R 62 = Independently C, U, or non-existent; R1, R2, R6, R9, R 10 , R 15 , R 19 , R 26 , R 38 , R 39 , R 46 , R 50 , R 51 , R 52 , R 64 , R 67 , R 69 = Independently G or non-existent; R 11 , R 16 = Independently G, U, or non-existent; R4, R7, R8, R 13 , R 21 , R 25, R 28 , R 29 , R 31 , 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.

[0628] In one embodiment, the TREM disclosed herein is Equation III PRO The array (sequence number 606), 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 Pro is, R0, R 17 , R 18 , R 22 , R 23 = non-existent; R 14 , R 45 , R 56 , R 57 , R 58 , R 65 , R 68 = Independently A or non-existent; R 37 = A, C, U, or non-existent; R 24 , R 27 , R 40 = Independently A, G, or non-existent; R3, R5, R 12 , R 30 , R 32 , R 48 , R 49 , R 55 , R 60 , R 61 , R 62 , R 66 , R 70 , R 71 , R 72 = Independently C or non-existent; R 34 , R 42 = Independently C, G, or non-existent; R 43 = C, G, U, or non-existent; R 41 = C, U, or non-existent; R1, R2, R6, R9, R 10 , R 15 , R 19 , R 20 , R 26 , R 33 , R 38 , R 39 , R 44 , R 46 , R 50 , R 51 , R 52 , R 63 , R 64 , R 67, R 69 = Independently G or non-existent; R 16 = G, U, or non-existent; R4, R7, R8, R 11 , R 13 , R 21 , R 25 , R 28 , R 29 , R 31 , R 35 , 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.

[0629] Serine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I SER The array (sequence number 607), 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 -R60 -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 Ser is, R0 = non-existence; R 14 , R 24 , R 57 = Independently A or non-existent; R 41 = A, C, or non-existent; R2, R3, R4, R5, R6, R7, R9, R 10 , R 11 , R 12 , R 13 , R 16 , R 21 , R 25 , R 26 , R 27 , R 28 , R 30 , R 31 , R 32 , R 33 , R 34 , R 37 , R 42 , R 43 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 = Independently N or non-existent; R 18 = A, C, U, or non-existent; R 15 , R 40, R 51 , R 56 = Independently A, G, or non-existent; R1, R 29 , R 58 , R 72 = Independently A, G, U, or non-existent; R 39 = A, U, or non-existent; R 60 = C or non-existent; R 38 = C, G, or non-existent; R 17 , R 22 , R 23 , R 71 = Independently C, G, U, or non-existent; R8, R 35 , R 36 , R 55 , R 59 , R 61 = Independently C, U, or non-existent; R 19 , R 20 = Independently G or non-existent; R 52 = G, U, or non-existent; 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.

[0630] In one embodiment, the TREM disclosed herein is Equation II SER The array (sequence number 608), 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 Ser is, R0, R 23 = non-existent, R 14 , R 24 , R 41 , R 57 = Independently A or non-existent; R 44 = A, C, or non-existent; R 25 , R 45 , R 48 = Independently A, C, G, or non-existent; R2, R3, R4, R5, R 37 , R 50 , R 62 , R 66 , R 67 , R 69 , R 70 = Independently N or non-existent; R 12 , R 28 , R 65 = Independently A, C, U, or non-existent; R9, R 15 , R 29 , R 34 , R 40 , R 56 , R 63 = Independently A, G, or non-existent; R7, R 26 , R 30 , R 33 , R 46 , R 58 , R 72 = Independently A, G, U, or non-existent; R 39 = A, U, or non-existent; R 11 , R 35 , R 60 , R 61 = Independently C or non-existent; R 13 , R 38 = Independently C, G, or non-existent; R6, R 17 , R 31 , R 43 , R 64 , R 68 = Independently C, G, U, or non-existent; R 36 , R 42 , R 49 , R 55 , R 59 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 27, R 51 = Independently G or non-existent; R1, R 16 , R 32 , R 52 = Independently G, U, or non-existent; R8, R 18 , R 21 , R 22 , 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.

[0631] In one embodiment, the TREM disclosed herein is Equation III SER Includes the sequence (sequence number 609), 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 Ser is, R0, R 23 = non-existent, R 14 , R 24 , R 41 , R 57 , R 58 = Independently A or non-existent; R 44 = A, C, or non-existent; R 25 , R 48 = Independently A, C, G, or non-existent; R2, R3, R5, R 37 , R 66 , R 67 , R 69 , R 70 = Independently N or non-existent; R 12 , R 28 , R 62 = Independently A, C, U, or non-existent; R7, R9, R 15 , R 29 , R 33 , R 34 , R 40 , R 45 , R 56 , R 63 = Independently A, G, or non-existent; R4, R 26 , R 46 , R 50 = Independently A, G, U, or non-existent; R 30 , R 39 = Independently A, U, or non-existent; R 11 , R 17 , R 35 , R 60 , R 61 = Independently C or non-existent; R 13 , R 38 = Independently C, G, or non-existent; R6, R 64 = Independently C, G, U, or non-existent; R 31 , R 42 , R 43 , R 49 , R 55 , R 59 , R 65 , R 68 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 27 , R 51 , R 52 = Independently G or non-existent; R1, R 16 , R 32 , R 72 = Independently G, U, or non-existent; R8, R 18 , R 21 , R 22 , 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.

[0632] Threonine TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I THR The array (sequence number 610), 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 -R20 -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 Thr is, R0, R 23 = non-existent; R 14 , R 41 , R 57 = Independently A or non-existent; R 56 , R70 = Independently A, C, G, or non-existent; R4, R5, R6, R7, R 12 , R 16 , R 26 , R 30 , R 31 , R 32 , R 34 , R 37 , R 42 , R 44 , R 45 , R 46 , R 48 , R 49 , R 50 , R 58 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 72 = Independently N or non-existent; R 13 , R 17 , R 21 , R 35 , R 61 = Independently A, C, U, or non-existent; R1, R9, R 24 , R 27 , R 29 , R 69 = Independently A, G, or non-existent; R 15 , R 25 , R 51 = Independently A, G, U, or non-existent; R 40 , R 53 = Independently A, U, or non-existent; R 33 , R 43 = Independently C, G, or non-existent; R2, R3, R 59 = Independently C, G, U, or non-existent; R 11 , R 18 , R 22 , R 28 , R 36 , R 54 , R 55 , R60 , R 71 = Independently C, U, or non-existent; R 10 , R 20 , R 38 , R 52 = Independently G or non-existent; R 19 = G, U, or non-existent; R8, R 39 = 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.

[0633] In one embodiment, the TREM disclosed herein is Equation II THR Includes the sequence (sequence number 611), 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 -R68 -R 69 -R 70 -R 71 -R 72 (In the formula, R is a ribonucleotide residue, and the consensus regarding Thr is, R0, R 18 , R 23 = non-existent, R 14 , R 41 , R 57 = Independently A or non-existent; R9, R 42 , R 44 , R 48 , R 56 , R 70 = Independently A, C, G, or non-existent; R4, R6, R 12 , R 26 , R 49 , R 58 , R 63 , R 64 , R 66 , R 68 = Independently N or non-existent; R 13 , R 21 , R 31 , R 37 , R 62 = Independently A, C, U, or non-existent; R1, R 15 , R 24 , R 27 , R 29 , R 46 , R 51 , R 69 = Independently A, G, or non-existent; R7, R 25 , R 45 , R 50 , R 67 = Independently A, G, U, or non-existent; R 40 , R 53 = Independently A, U, or non-existent; R 35 = C or non-existent; R 33 , R 43 = Independently C, G, or non-existent; R2, R3, R5, R 16 , R 32 , R 34 , R 59 , R 65 , R 72 = Independently C, G, U, or non-existent; R 11 , R 17 , R 22 , R 28 , R 30 , R 36 , R 55 , R 60 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 38 , R 52 = Independently G or non-existent; R8, R 39 , 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.

[0634] In one embodiment, the TREM disclosed herein is Equation III THR The array (sequence number 612), 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 Thr is, R0, R 18 , R 23 = non-existent, R 14 , R 40 , R 41 , R 57 = Independently A or non-existent; R 44= A, C, or non-existent; R9, R 42 , R 48 , R 56 = Independently A, C, G, or non-existent; R4, R6, R 12 , R 26 , R 58 , R 64 , R 66 , R 68 = Independently N or non-existent; R 13 , R 21 , R 31 , R 37 , R 49 , R 62 = Independently A, C, U, or non-existent; R1, R 15 , R 24 , R 27 , R 29 , R 46 , R 51 , R 69 = Independently A, G, or non-existent; R7, R 25 , R 45 , R 50 , R 63 , R 67 = Independently A, G, U, or non-existent; R 53 = A, U, or non-existent; R 35 = C or non-existent; R2, R 33 , R 43 , R 70 = Independently C, G, or non-existent; R5, R 16 , R 34 , R 59 , R 65 = Independently C, G, U, or non-existent; R3, R 11 , R 22 , R 28 , R 30 , R 36 , R 55 , R 60 , R 61 , R 71 = Independently C, U, or non-existent; R 10 , R 19 , R 20 , R 38 , R 52 = Independently G or non-existent; R 32 = G, U, or non-existent; R8, R 17 , R 39 , R 54 , R 72 = 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.

[0635] Tryptophan TREM consensus sequence In one embodiment, the TREM disclosed herein is of formula I TRP The array (sequence number 613), 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 Trp is, R0 = non-existence; R 24 , R 39 , R 41 , R 57 = Independently A or non-existent; R2, R3, R 26 , R 27 , R 40 , R 48 = Independently A, C, G or non-existent; R4, R5, R6, R 29 , R 30 , R 31 , R 32 , R 34 , R 42 , R 44 , R 45 , R 46 , R 49 , R 51 , R 58 , R 63 , R 66 , R 67 , R 68 = Independently N or non-existent; R 13 , R 14 , R 16 , R 18 , R 21 , R 61 , R 65 , R 71 = Independently A, C, U, or non-existent; R1, R9, R 10 , R 15 , R 33 , R 50 , R 56 = Independently A, G, or non-existent; R7, R 25 , R 72 = Independently A, G, U, or non-existent; R 37 , R 38, R 55 , R 60 = Independently C or non-existent; R 12 , R 35 , R 43 , R 64 , R 69 , R 70 = Independently C, G, U, or non-existent; R 11 , R 17 , R 22 , R 28 , R 59 , R 62 = Independently C, U, or non-existent; R 19 , R 20 , R 52 = Independently G or non-existent; R8, R 23 , 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.

[0636] In one embodiment, the TREM disclosed herein is Equation II TRP The array (sequence number 614), 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 Trp is, R0, R 18 , R 22 , R 23 = non-existent; R 14 , R 24 , R 39 , R 41 , R 57 , R 72= Independently A or non-existent; R3, R4, R 13 , R 61 , R 71 = Independently A, C, or non-existent; R6, R 44 = Independently A, C, G, or non-existent; R 21 = A, C, U, or non-existent; R2, R7, R 15 , R 25 , R 33 , R 34 , R 45 , R 56 , R 63 = Independently A, G, or non-existent; R 58 = A, G, U, or non-existent; R 46 = A, U, or non-existent; R 37 , R 38 , R 55 , R 60 , R 62 = Independently C or non-existent; R 12 , R 26 , R 27 , R 35 , R 40 , R 48 , R 67 = Independently C, G, or non-existent; R 32 , R 43 , R 68 = Independently C, G, U, or non-existent; R 11 , R 16 , R 28 , R 31 , R 49 , R 59 , R 65 , R 70 = Independently C, U, or non-existent; R1, R9, R 10 , R 19 , R 20 , R 50 , R 52 , R 69 = Independently G or non-existent; R2, R8, R 29 , R 30 , R 42 , R 51 , R 64 , R 66 = Independently G, U, or non-existent; R 17 , 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 contain...

Claims

[Claim 1] The invention described herein.

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