Polypeptidyl Linker

Abstract

Provided herein are compounds of formula (I) and (II) that contain a polypeptidyl group. Also provided herein are methods for preparing compounds of formula (I) and (II). Further provided herein are methods for sequencing polypeptides by reacting compounds of formula (II) with peptidase.

Description

[Technical Field]

[0001] The present invention relates to polypeptidyl linkers. [Background technology]

[0002] Proteomics has emerged as an important and necessary complement to genomics and transcriptomics in the study of biological systems. Proteomic analysis of individual organisms can provide insight into cellular processes and response patterns, which can lead to improved diagnostic and therapeutic strategies. The complexity surrounding protein structure, composition, and modifications presents challenges in determining large-scale protein sequencing information for biological samples.

[0003] Previous research has developed methods for determining polypeptide sequences by using the degradation process of polypeptides by peptidases to generate amino acid sequences representative of the resulting polypeptides. See, for example, U.S. Patent Application Publication No. 2019 / 0129999, filed November 15, 2019, and U.S. Patent Application Publication No. 2021 / 0129999, filed May 20, 2021, each of which is incorporated by reference in its entirety. As the degradation process progresses during such sequencing, the length of the polypeptide decreases. Therefore, the ability of the polypeptide to access the active site of the peptidase becomes increasingly inefficient, resulting in a decrease in cleavage efficiency (e.g., cleavage rate), cleavage depth, and information content of the read. There is a need to develop strategies to overcome these challenges in polypeptide sequencing. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2020 / 102741 [Patent Document 2] International Publication No. 2021 / 236983 Summary of the Invention [Means for solving the problem]

[0005] In such methods of polypeptide sequencing, polypeptides are linked to oligonucleotides via linkers, which together can be used to increase solubility and enable surface immobilization. One strategy to overcome the challenges associated with these methods is to modify the structure of the linker, which affects many parameters related to polypeptide sequencing, including conjugation rate, conjugation bias, conjugate aggregation, cleavage kinetics, and pulse width. At the molecular level, the structure of the linker can affect the solvation of the polypeptide, the distance between the polypeptide and the oligonucleotide, and the potential secondary structure adopted by the polypeptide. The secondary structure adopted by a polypeptide can be influenced by non-covalent interactions within the polypeptide, between the polypeptide and the linker, and / or between the polypeptide and the oligonucleotide. Factors related to secondary structure include the length, polarity, size, bulkiness, charge, and rigidity or flexibility of the linker, as well as the stability of the terminal base pairs.

[0006] This application describes novel linkers, as well as methods for their preparation. These novel linkers can be coupled to polypeptides, including via click chemistry reactions, to form linker-polypeptide conjugates that are useful for sequencing polypeptides. The novel linkers offer several advantages, including improved cleavage efficiency, cleavage depth, and information content of leads.

[0007] Thus, in one embodiment, a compound of formula (I): LY(I) Provided herein is a compound of the formula: wherein L and Y are defined herein, or a salt thereof.

[0008] In another embodiment, a compound of formula (II): ZLY(II) Provided herein are compounds of the formula: wherein L, Y, and Z are defined herein, or a salt thereof.

[0009] In another embodiment, a compound of formula (I): LY(I) or a salt thereof, with a compound of formula Z-N3 or a salt thereof, Formula (II): ZLY(II) or a salt thereof, wherein L, Y, and Z are defined herein.

[0010] In another embodiment, there is provided a method for sequencing a polypeptide Z, comprising the step of: ZLY(II) or a salt thereof, wherein L and Y are defined herein, with a peptidase; In the degradation process, reacting the compound of formula (II) or a salt thereof with a peptidase; acquiring data during the decomposition process; analyzing the data to determine portions of the data corresponding to amino acids that are sequentially exposed at the termini of the polypeptide during the degradation process; Provided herein is a method for sequencing polypeptide Z, comprising:

[0011] Details of certain embodiments of the present disclosure are set forth in the Detailed Description of Certain Embodiments, as set forth below. Other features, objects, and advantages of the present disclosure will be apparent from the definitions, examples, and claims. [Brief explanation of the drawings]

[0012] [Figure 1A] The structure of the C6 linker is shown. [Figure 1B]

[0033] Figure 1 shows the structure of the aspartic acid-rich Q24D linker (SEQ ID NO: 43). Based on the TET aminopeptidase structural model, the minimum distance required for the linker is 33 Å. [Figure 1C] 1 shows improved access to the aminopeptidase active site of the Q24D linker compared to the C6 linker. [Figure 2] The predicted structure of Q24-sulfo-PEG3-DBCO is shown, which indicates that DBCO can be enveloped by the PEG spacer, making it inaccessible to solvent, and that long, flexible spacers, polar or not, can slow the conjugation rate between DBCO and polypeptides via the click reaction. [Figure 3A] The predicted structure of Q24-EGWRW-DBCO (SEQ ID NO: 48) is shown, indicating that EGWRW (SEQ ID NO: 48) forms a sacrificial spacer to lift DBCO from the DNA end, one tryptophan side chain stacks on the terminal base pair, the other tryptophan side chain stacks on DBCO, and the arginine intercalates in the major groove of the duplex. [Figure 3B] The arginine-base distance for Q24-EGWRW-DBCO (SEQ ID NO: 48) is shown. [Figure 4A] 4A-4B show the predicted starting structure (FIG. 4A) and relaxed structure (FIG. 4B) of Q24-QP423 containing a C6 linker. [Figure 4B] Same as above. [Figure 5A] Figures 5A-5B show the predicted starting structure (Figure 5A) and relaxed structure (Figure 5B) of Q24D-QP423, which contains the DBCO-DDGGGDDDFFK(N3) (SEQ ID NO: 44) polypeptidyl linker. There are no arginine-DNA interactions. [Figure 5B] Same as above. [Figure 6] Arginine-base distances are shown for Q24-QP423 (blue, with a C6 linker) and Q24D-QP423 (orange, with a DBCO-DDGGGDDDFFK(N3) (SEQ ID NO: 44) polypeptidyl linker). [Figure 7A] Figures 7A-7B show protein structure-based designs using TET aminopeptidase and either the linker DBCO-GGSSSGSGNDEEFQK(N3)-Q24 (SEQ ID NO: 60) (Figure 7A) or the linker DBCO-GGGGGGDPDPDK(N3)-Q24(Q24GDP) (SEQ ID NO: 58) (Figure 7B). [Figure 7B] Same as above. [Figure 8A] Figures 8A-8B show the cleavage rates of QP423 with different linkers using hTet / pfuTet as the cutter. Figure 8A shows the relative cleavage rates normalized to the C6 linker. N linker sequence: NNGGGDDDFFK (SEQ ID NO: 64); GDP linker sequence: GGGGGGDPDPDK (SEQ ID NO: 58); GDPF linker sequence: GGGGGDPDPDFFK (SEQ ID NO: 56); D linker sequence: DDGGGDDDFFK (SEQ ID NO: 44). Figure 8B shows the relative cleavage rates normalized to the D linker. Cleavage of the first residue, R, is too rapid in AP30 / AP37 to assess the relative rate for the Cy spacer. [Figure 8B] Same as above. [Figure 9-1] The Q24D linker improves cut depth, with a 76% improvement in average cut depth and a 3-fold increase in 3+ RS reads. [Figure 9-2] Same as above. [Figure 9-3] Same as above. [Figure 10] The sample-prep compatible Q24D linker is shown to greatly enhance cleavage (SEQ ID NO: 50). [Figure 11A]Figures 11A-11E show improved sequencing performance with the Q24D linker compared to the C6 linker, with a longer cleavage depth and, on average, more amino acids recognized in the trace. Figures 11A-11D show traces corresponding to four peptides resulting from digestion of the recombinant human protein CDNF (brain dopamine neurotrophic factor, 161 amino acids): EFLNRFYK (SEQ ID NO: 47) (Figure 11A), ELISFCLDTK (SEQ ID NO: 49) (Figure 11B), TDYVNLIQELAPK (SEQ ID NO: 69) (Figure 11C), and SLIDRGVNFSLDTIEK (SEQ ID NO: 68) (Figure 11D). Figure 11E shows that software analysis successfully identified substantially more reads corresponding to each peptide with QL581 (containing the Q24D linker) compared to QL580 (containing the C6 linker). [Figure 11B] Same as above. [Figure 11C] Same as above. [Figure 11D] Same as above. [Figure 11E] Same as above. [Figure 12] An illustrative overview of real-time dynamic protein sequencing is shown. Protein samples are digested into peptide fragments, immobilized in a nanoscale reaction chamber, and incubated with a mixture of freely diffusing N-terminal amino acid (NAA) recognition factors and aminopeptidases (SEQ ID NOs: 67 and 63) that perform the sequencing process. Labeled recognition factors bind to peptides on and off when one of their cognate NAAs is exposed at the N-terminus, thereby generating a characteristic pulse pattern. The NAA is cleaved by the aminopeptidase, exposing the next amino acid for recognition. The temporal order and binding kinetics of NAA recognition enable peptide identification and are sensitive to features that modulate binding kinetics, such as post-translational modifications (PTMs). DETAILED DESCRIPTION OF THE INVENTION

[0013] definition The definitions of specific functional groups and chemical terms are described in more detail below.Chemical elements are identified according to the Periodic Table of Elements, CAS version, and the inside cover of the 75th edition of "Handbook of Chemistry and Physics", and specific functional groups are generally defined as described herein.In addition, the general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March's Advanced Organic Chemistry, 7th edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0014] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, IN, 1972). The present invention further encompasses the compounds as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0015] Unless otherwise stated, the formulas and structures depicted herein include compounds that do not contain isotopically enriched atoms, as well as compounds that contain isotopically enriched atoms, e.g., replacement of hydrogen with deuterium or tritium, 19 F 18 Substitution to F, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0016] When a range of values ​​("range") is listed, it is intended to encompass each value and sub-range within the range. A range includes both endpoints of the range unless otherwise specified. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It includes alkyl.

[0017] When a range of values ​​("range") is listed, it is intended to encompass each value and subrange within the range. A range includes both endpoints of the range unless otherwise specified. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It includes alkyl.

[0018] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Similarly, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0019] The term "alkyl" refers to the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C9), and hexyl (C10).12 Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, an alkyl group is an unsubstituted C 1-12 Alkyl (e.g., unsubstituted C 1-6 Alkyl, for example, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1-12 Alkyl (e.g., substituted C 1-6 alkyl, for example, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn), etc.

[0020] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. "Perhaloalkyl" is a subset of haloalkyl and refers to an alkyl group in which all of the hydrogen atoms are independently replaced with a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms ("C 1-20 In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms ("C 1-10 In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms ("C 1-9 In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1-8 In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms ("C 1-7In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1-6 In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms ("C 1-5 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1-4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1-3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1-2 In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a "perfluoroalkyl" group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a "perchloroalkyl" group. Examples of haloalkyl groups include -CHF, -CHF, -CF, -CHCF, -CFCF, -CFCF, -CFCFCF, -CCl, -CFCl, -CFCl, and the like.

[0021] The term "heteroalkyl" refers to an alkyl group that contains at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the parent chain (e.g., inserted between adjacent carbon atoms of the parent chain) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 20 carbon atoms and one or more heteroatoms in the parent chain ("heteroC"). 1-20 In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 12 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-12 In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-11In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-7 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, it is a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-3 In some embodiments, it is a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1-2 In some embodiments, heteroalkyl refers to a saturated group having 1 carbon atom and one or more heteroatoms in the parent chain ("heteroC1 alkyl"). In some embodiments, heteroalkyl refers to a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 2-6Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-12 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-12 It is alkyl.

[0022] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkenyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkenyl group has 1 to 11 carbon atoms ("C 1-11 In some embodiments, an alkenyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkenyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkenyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkenyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkenyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkenyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkenyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkenyl group has 1 to 3 carbon atoms ("C 1-3In some embodiments, an alkenyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkenyl group has one carbon atom ("C1 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 1-4 Examples of alkenyl groups include methylidenyl (C1), ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 1-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 1-20 In certain embodiments, the alkenyl group is a substituted C 1-20 In an alkenyl group, a C=C double bond with unspecified stereochemistry (e.g., -CH=CHCH3 or

[0023] [ka]

[0024] ) can be in the (E)- or (Z)-configuration. The term "heteroalkenyl" refers to an alkenyl group that further contains at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located internally (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having 1 to 20 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl"). 1-20 In certain embodiments, a heteroalkenyl group refers to a group having 1 to 12 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1-12 In certain embodiments, a heteroalkenyl group refers to a group having 1 to 11 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1-11 In certain embodiments, a heteroalkenyl group refers to a group having 1 to 10 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, heteroalkenyl groups have 1 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1-9 In some embodiments, heteroalkenyl groups have 1 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, heteroalkenyl groups have 1 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1-7 In some embodiments, heteroalkenyl groups have 1 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 1-6In some embodiments, heteroalkenyl groups have 1 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5 In some embodiments, heteroalkenyl groups have 1 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkenyl groups have 1 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 1-3 In some embodiments, heteroalkenyl groups have 1 to 2 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 1-2 In some embodiments, heteroalkenyl groups have 1 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 1-20 In certain embodiments, the heteroalkenyl group is a substituted heteroC 1-20 It is alkenyl.

[0025] The term "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 1-20 In some embodiments, an alkynyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkynyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkynyl group has 1 to 8 carbon atoms ("C1-8 In some embodiments, an alkynyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkynyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkynyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkynyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkynyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkynyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkynyl group has one carbon atom ("C1 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 1-4 Examples of alkynyl groups include, but are not limited to, methylidinyl (C1), ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 1-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 1-20 In certain embodiments, the alkynyl group is a substituted C 1-20 It is alkynyl.

[0026] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within the alkynyl group (e.g., inserted between adjacent carbon atoms) and / or at one or more terminal positions of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having 1 to 20 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 1-20 In certain embodiments, a heteroalkynyl group refers to a group having 1 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1-10 In some embodiments, heteroalkynyl groups have 1 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1-9 In some embodiments, heteroalkynyl groups have 1 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1-8 In some embodiments, heteroalkynyl groups have 1 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1-7 In some embodiments, heteroalkynyl groups have 1 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 1-6 In some embodiments, heteroalkynyl groups have 1 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1-5 In some embodiments, heteroalkynyl groups have 1 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1-4 In some embodiments, heteroalkynyl groups have 1 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC1-3 In some embodiments, heteroalkynyl groups have 1 to 2 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 1-2 In some embodiments, heteroalkynyl groups have 1 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 1-6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 1-20 In certain embodiments, the heteroalkynyl group is a substituted heteroC 1-20 It is alkynyl.

[0027] The term "carbocyclyl" or "carbocyclic" refers to a ring of 3 to 14 carbon atoms ("C 3-14 In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms ("C 3-13 In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms ("C 3-12 In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms ("C 3-11 In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3-8 The carbocyclyl group includes the aforementioned C 3-6 Included are carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group includes the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and others. 3-8 The carbocyclyl group includes the aforementioned C 3-10 The bocyclyl group, as well as the cycloundecyl (C 11 ), spiro[5.5]undecanyl (C 11), cyclododecyl (C 12 ), cyclododecenyl (C 12 ), cyclotridecane (C 13 ), cyclotetradecane (C 14 ) and the like. In certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocycle") or polycyclic (including, for example, fused, bridged, or spiro ring systems such as a bicyclic ring system ("bicyclic carbocyclyl") or a tricyclic ring system ("tricyclic carbocyclyl")), and may be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups whose points of attachment are on the carbocyclyl ring; in such cases, the number of carbons continues to indicate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-14 In certain embodiments, the carbocyclyl group is a substituted C 3-14 It is a carbocyclyl.

[0028] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 14 ring carbon atoms ("C 3-14 In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3-14 In certain embodiments, the cycloalkyl group is a substituted C 3-14 In certain embodiments, a carbocyclyl contains, where valence allows, 0, 1, or 2 C=C double bonds in the carbocyclic ring system.

[0029] The terms "heterocyclyl" or "heterocyclic" refer to the radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valence allows. Heterocyclyl groups can be either monocyclic (a "monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as a bicyclic system (a "bicyclic heterocyclyl") or a tricyclic system (a "tricyclic heterocyclyl")), saturated, or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 14-membered heterocyclyl. In certain embodiments, the heterocyclyl is a substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, where one, two, or three atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valence allows.

[0030] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0031] Exemplary 3-membered heterocyclyl groups containing one heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1, 4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0032] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 pi electrons in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to refer to the number of carbons in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0033] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, where the point of attachment is on the alkyl portion. The term "heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, valence permitting. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups whose points of attachment are on the heteroaryl ring; in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring defined above is fused to one or more aryl groups, with the point of attachment being either on the aryl or heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups, one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), and the point of attachment can be on either ring, e.g., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is a substituted or unsubstituted 5- or 6-membered monocyclic heteroaryl, and one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is a substituted or unsubstituted 9- or 10-membered bicyclic heteroaryl, and one, two, three, or four atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0034] In some embodiments, heteroaryl groups are 5-10 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0035] Exemplary 5-membered heteroaryl groups containing one heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0036] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, where the point of attachment is on the alkyl portion. The term "unsaturated bond" refers to a double or triple bond.

[0037] The terms "unsaturated" or "partially unsaturated" refer to a moiety that contains at least one double or triple bond. The term "saturated" or "fully saturated" refers to a moiety that does not contain any double or triple bonds, e.g., the moiety contains only single bonds.

[0038] The addition of the suffix "-ene" indicates that the group is a divalent moiety, for example, alkylene is a divalent moiety of alkyl, alkenylene is a divalent moiety of alkenyl, alkynylene is a divalent moiety of alkynyl, heteroalkylene is a divalent moiety of heteroalkyl, heteroalkenylene is a divalent moiety of heteroalkenyl, heteroalkynylene is a divalent moiety of heteroalkynyl, carbocyclylene is a divalent moiety of carbocyclyl, heterocyclylene is a divalent moiety of heterocyclyl, arylene is a divalent moiety of aryl, and heteroarylene is a divalent moiety of heteroaryl.

[0039] Unless otherwise specified, a group is optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a substituted or unsubstituted group (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" heteroalkyl, a "substituted" or "unsubstituted" heteroalkenyl, a "substituted" or "unsubstituted" heteroalkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen atom present on a group is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any given structure are substituted, the substituents are either the same or different at each position. The term "substituted" is considered to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. The present invention is in no way limited by the exemplary substituents described herein.

[0040] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)R aa , -Si(R aa)3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(R cc )4、-OP(OR cc )4、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc )、C 1-20 アルキル、C 1-20 ペルハロアルキル、C 1-20 アルケニル、C 1-20Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; - is a counterion; Or the two geminal hydrogens on a carbon atom are =O, =S, =NN(R bb )2, =NN(R bb )2, =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc substituted with a group; R aa Each instance of is independently 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R aa groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups; Rbb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc ), -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R bb groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups; R cc Each instance of is independently hydrogen, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl C 1-20 Alkynyl, Hetero C1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, or two R cc groups join to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(Rff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents are bonded to form =O or =S; X - is the counterion; R ee Each instance of 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, or two R groups joined to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 Alkyl 2, -N(C 1-6 Alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3+ X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)(OC 1-6 alkyl)2, -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 1-10 Alkenyl, C 1-10 Alkynyl, Hetero C 1-10 Alkyl, Hetero C 1-10 Alkenyl, Hetero C 1-10 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 5- to 10-membered heteroaryl; or two geminal R gg groups can be linked to form =O or =S, each X - is the counterion.

[0041] In certain embodiments, each carbon atom is independently a halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO22R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NRbb C(=O)N(R bb In certain embodiments, each carbon atom is independently a halogen, substituted (e.g., substituted with one or more halogens), or unsubstituted C 1-10 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , or -NR bb C(=O)N(R bb )2, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, an oxygen protecting group when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or a sulfur protecting group when attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl); and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 In certain embodiments, each carbon atom substituent is independently a halogen, a substituted (e.g., substituted with one or more halogens) or an unsubstituted C 1-6 Alkyl, -OR aa , -SR aa , -N(R bb)2, -CN, -SCN, or -NO2. In certain embodiments, each carbon atom substituent is independently a halogen, a substituted (e.g., substituted with one or more halogens) or an unsubstituted C 1-10 Alkyl, -OR aa , -SR aa , -N(R bb )2, -CN, -SCN, -NO2, where R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, an oxygen protecting group when attached to an oxygen atom (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl), or a sulfur protecting group when attached to a sulfur atom (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridinesulfenyl, or triphenylmethyl); and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0042] In certain embodiments, the molecular weight of the carbon atom substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In certain embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, the carbon atom substituent is composed of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0043] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I). The term "hydroxyl" or "hydroxy" refers to an -OH group. The term "substituted hydroxyl" or "substituted hydroxyl" by extension refers to a hydroxyl group in which the oxygen atom directly attached to the parent molecule has been replaced with a group other than hydrogen, such as -OR aa , -ON(R bb )2, -OC(=O)SR aa , -OC(=O)R aa , -OCO 2 R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OSi(R aa )3, -OP(R cc )2, -OP(R cc )3 + X - , -OP(OR cc )2, -OP(OR cc )3 + X - , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, and -OP(=O)(N(R bb ))2, wherein X - , R aa , R bb and R cc is as defined herein.

[0044] The term "thiol" or "thio" refers to an -SH group. The term "substituted thiol" or "substituted thio" by extension refers to a thiol group in which the sulfur atom directly attached to the parent molecule has been replaced with a group other than hydrogen, such as -SR aa, -S=SR cc , -SC(=S)SR aa , -SC(=S)OR aa , -SC(=S)N(R bb )2, -SC(=O)SR aa , -SC(=O)OR aa , -SC(=O)N(R bb )2, and -SC(=O)R aa wherein R aa and R cc is as defined herein.

[0045] The term "amino" refers to the group -NH. The term "substituted amino" extends to mono-, di-, or tri-substituted amino. In certain embodiments, a "substituted amino" is a mono- or di-substituted amino group.

[0046] The term "monosubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with one hydrogen and one non-hydrogen group, -NH(R bb ), -NHC(=O)R aa , -NHCO2R aa , -NHC(=O)N(R bb )2, -NHC(=NR bb )N(R bb )2, -NHSO2R aa , -NHP(=O)(OR cc )2, and -NHP(=O)(N(R bb )2)2, wherein R aa , R bb and R cc is as defined herein, and —NH(R bb ) group R bb is not hydrogen.

[0047] The term "disubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is replaced with two groups other than hydrogen, -N(R bb )2, -NR bb C(=O)Raa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -NR bb SO2R aa , -NR bb P(=O)(OR cc )2, and -NR bb P(=O)(N(R bb )2)2, wherein R aa , R bb and R cc is as defined herein, provided that the nitrogen atom directly attached to the parent molecule is not replaced with a hydrogen.

[0048] The term "trisubstituted amino" refers to an amino group in which the nitrogen atom directly attached to the parent molecule is substituted with three groups, -N(R bb )3 and -N(R bb )3 + X - wherein R bb and X - is as defined herein.

[0049] The term "sulfonyl" refers to -SO2N(R bb )2, -SO2R aa , and -SO2OR aa where R aa and R bb is as defined herein.

[0050] The term "sulfinyl" refers to -S(=O)R aa refers to the group, where R aa is as defined herein. The term "acyl" refers to a group having the general formula: -C(=O)R X1 , -C(=O)OR X1, -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, and -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , and -C(=NR X1 )N(R X1 )2, where R X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R X1The groups taken together form a 5- to 6-membered heterocycle. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thioxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphatic amino, heteroaliphatic amino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, etc., each of which may be further substituted or unsubstituted).

[0051] The term "carbonyl" refers to the carbon directly attached to the parent molecule being sp 2 Hybridized groups substituted with oxygen, nitrogen, or sulfur atoms, such as ketones (-C(=O)R aa ), carboxylic acid (-CO2H), aldehyde (-CHO), ester (-CO2R aa , -C(=O)SR aa , -C(=S)SR aa ), amide (-C(=O)N(R bb )2, -C(=O)NR bb SO2R aa , -C(=S)N(R bb )2), and imine (-C(=NR bb )R aa , -C(=NR bb ) OR aa ), -C(=NR bb )N(R bb ) 2) wherein R aa and Rbb is as defined herein.

[0052] The term "silyl" refers to the group -Si(R aa )3, where R aa is as defined herein. The term “boronyl” refers to borane, boronic acid, boronic ester, borinic acid, and borinic acid ester, such as those of the formula —B(R aa )2, -B(OR cc )2, and -BR aa (OR cc ) refers to the boronyl group of the formula aa and R cc is as defined herein.

[0053] The term "phosphino" refers to -P(R cc ) groups, where R cc is as defined herein. The term "phosphono" refers to -(P=O)(O cc ) groups, where R aa and R cc is as defined herein.

[0054] The term "phosphoramide" refers to -O(P=O)(N(R bb )2) refers to two groups, where each R bb is as defined herein. The term "oxo" refers to the group =O and the term "thiooxo" refers to the group =S.

[0055] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2Raa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(OR cc )2, -P(=O)(R aa )2, -P(=O)(N(R cc )2)2, C 1-20 Alkyl, C 1-20 Perhaloalkyl, C 1-20 Alkenyl, C 1-20 Alkynyl, Hetero C 1-20 Alkyl, Hetero C 1-20 Alkenyl, Hetero C 1-20 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 Aryl and 5- to 14-membered heteroaryl, or two R groups attached to a N atom cc groups join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc and R dd The groups are as defined above.

[0056] In certain embodiments, each nitrogen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(Rbb )2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently a substituted (substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a nitrogen protecting group, and R aa is hydrogen, substituted (with one or more halogens) or unsubstituted C 1-10 alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bb are independently hydrogen, substituted (with one or more halogens) or unsubstituted C 1-10 In certain embodiments, each nitrogen atom substituent is independently a substituted (substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or nitrogen protecting group.

[0057] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 1-20 Alkenyl, C 1-20 Alkynyl, hetero 1-20Alkyl, hetero 1-20 Alkenyl, hetero 1-20 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl may have 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc , and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in "Protecting Groups in Organic Synthesis", T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0058] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a nitrogen protecting group (e.g., —C(═O)R aaIn certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacet ... amide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0059] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a nitrogen protecting group (e.g., —C(═O)OR aaIn certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-T moc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl Carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate Carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-Dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate mate (Peoc), 2-triphenylphosphonioiisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-di Methoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N -dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborinyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

[0060] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a nitrogen protecting group (e.g., —S(═O)R aa In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4, 6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0061] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which it is attached, independently represents a phenothiazinyl-(10)-acyl derivative, an N'-p-toluenesulfonylaminoacyl derivative, an N'-phenylaminothioacyl derivative, an N-benzoylphenylalanyl derivative, an N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-diphenyl-3-oxazolin-2-one, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, N-phenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-diphenyl-3-oxazolin-2-one, N- ... -Dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl)-2-methyl-2-methyl-1,3,5-triazacyano-4-one, N ...allyl-2-methyl-1,3,5-triazacyano-4-one, N-(2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl)-2-methyl-1,3,5-triazacyano-4-one, N-(1-isopropyl)-2-methyl-1,3,5-triazacyano-4-one, N-(1-isopropyl)-2-methyl-1,3,5-triazacyano-4-one, N-(1-isopropyl)-2-methyl-1,3,5-triazacyano-4-one, N-(1-isopropyl)-2-methyl-1,3,5-triazacyano-4- Pyr-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolyl Amino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacychromium or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide and 3-nitropyridine sulfenamide (Npys). In some embodiments, two examples of nitrogen protecting groups, together with the nitrogen atom to which they are attached, are N,N'-isopropylidenediamine.

[0062] In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or an oxygen protecting group, and R aa is a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bbare independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 In certain embodiments, each oxygen atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 It is an alkyl or oxygen protecting group.

[0063] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )2 + X - , -P(OR cc )2, -P(OR cc )2 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, where X - , R aa , R bb , and R ccis as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in "Protecting Groups in Organic Synthesis", T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0064] In certain embodiments, each oxygen protecting group, together with the oxygen to which it is attached, is selected from the group consisting of methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, and 4-methoxytetrahydrothiopyranyl. S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy -2-Fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxide, diphenyloxymethyl, p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, 4,4'-dimethoxytrityl (4,4'-dimethoxytriphenylmethyl,DMTr or DMT), α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4''-tris(benzoyloxyphenyl)methyl, 4,4'-dimethoxy-3'''-[N-(imidazoline)- [N-(imidazolemethyl)]trityl ether (IDTr-OR), 4,4'-dimethoxy-3'''-[N-(imidazolemethyl)carbamoyl]trityl ether (IETr-OR), 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate Salt, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-Trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate , p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoic acid, 4-azidobutyrate, 4-nitro-4-methylpentanoic acid, o-(dibromomethyl)benzoic acid, 2-formylbenzenesulfonic acid, 2-( The alkyl group may be selected from the group consisting of alkyl methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoic acid, 2,6-dichloro-4-methylphenoxyacetic acid, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid, chlorodiphenylacetic acid, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0065] In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0066] In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 Alkyl, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, or a sulfur protecting group, and R aa is hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 alkyl, or, if attached to an oxygen atom, an oxygen protecting group, and each R bb are independently hydrogen, substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-10 In certain embodiments, each sulfur atom substituent is independently a substituted (e.g., substituted with one or more halogens) or unsubstituted C 1-6 alkyl, or sulfur protecting groups.

[0067] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). In some embodiments, each sulfur protecting group is -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(ORcc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, wherein R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in "Protecting Groups in Organic Synthesis", T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0068] In certain embodiments, the molecular weight of the substituent is less than 250 g / mol, less than 200 g / mol, less than 150 g / mol, less than 100 g / mol, or less than 50 g / mol. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, the substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms. In certain embodiments, the substituent comprises 0, 1, 2, or 3 hydrogen bond donors. In certain embodiments, the substituent comprises 0, 1, 2, or 3 hydrogen bond acceptors.

[0069] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., containing one formal negative charge). An anionic counterion may be multivalent (e.g., containing two or more formal negative charges), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F - , Cl- , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) - Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutarate, etc.) and carboranes.

[0070] "Leaving group" (LG) is an art-recognized term that refers to an atom or molecular fragment that departs with an electron pair in a heterolytic bond cleavage, where the molecular fragment is an anion or a neutral molecule. As used herein, a leaving group can be an atom or group that can be displaced by a nucleophile. See, for example, Smith, "March Advanced Organic Chemistry," 6th Edition, pp. 501-502. Exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -OC(=O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2, and -OP(=O)(NR bb )2), where R aa , R bb , and R ccis as defined herein. Further examples of suitable leaving groups include, but are not limited to, halogen, alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some embodiments, the leaving group is a sulfonate ester such as toluenesulfonic acid (tosylate, -OTs), methanesulfonic acid (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some embodiments, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some embodiments, the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group is a sulfonate-containing group. In some embodiments, the leaving group is a tosylate group. In some embodiments, the leaving group is an internal leaving group such as a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an epoxide or a cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties.

[0071] Use of the phrase "at least one instance" refers to 1, 2, 3, 4, or more instances, but also encompasses ranges of, for example, 1-4, 1-3, 1-2, 2-4, 2-3, or 3-4 instances.

[0072] "Non-hydrogen group" refers to any group defined for a particular variable that is not hydrogen. These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not limited in any way by the recitation of exemplary substituents above.

[0073] As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts. Salts include ionic compounds resulting from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions), such that the salt is electrically neutral (has no net charge). Salts of the compounds of the present invention include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, hydroxybenzo ... Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-toluenesulfonates.+ (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0074] As used herein, the term "work-up" refers to a single step or a series of steps directed to isolating and / or purifying one or more products of a chemical reaction (e.g., from remaining starting materials, other reagents, solvents, or by-products of a chemical reaction). Reaction work-up may include removing solvents, for example, by evaporation or lyophilization. Reaction work-up may also include performing liquid-liquid extraction, for example, by separating the reaction mixture into organic and aqueous layers. In some embodiments, reaction work-up includes quenching the reaction to inactivate any unreacted reagents. Reaction work-up may also include cooling the reaction mixture to induce precipitation of solids from the mixture, which may be collected or removed, for example, by filtration, decantation, or centrifugation. Reaction work-up may also include purification of one or more products of the reaction by chromatography. Other methods, including, but not limited to, distillation and recrystallization, may also be used to purify one or more reaction products. Other processes for working up reactions are known in the art, and one of ordinary skill in the art can readily determine other suitable methods that can be used in working up a particular reaction.

[0075] As used herein, the term "about X" or "approximately X" (where X is a number or percentage) refers to a number or percentage that is 99.5% to 100.5%, 99% to 101%, 98% to 102%, 97% to 103%, 96% to 104%, 95% to 105%, 92% to 108%, or 90% to 110% of X (all ranges inclusive of X).

[0076] The terms "polynucleotide," "nucleotide sequence," "nucleic acid," "nucleic acid molecule," "nucleic acid sequence," and "oligonucleotide" refer to a series of nucleotide bases (also called "nucleotides") in DNA and RNA, and refer to any chain of two or more nucleotides. Polynucleotides can be chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. Oligonucleotides can be modified at the base moiety, sugar moiety, or phosphate backbone to improve, for example, the molecule's stability, its hybridization parameters, etc. Antisense oligonucleotides include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, β-D-galactosyl eosin, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, and 5-methylaminomethyl The modified base moiety may be selected from the group including, but not limited to, uracil, 5-methoxyaminomethyl-2-thiouracil, β-D-mannosyl euosin, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, wybutoxocin, pseudouracil, queosin, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, 5-oxyacetic acid methyl ester, uracil-5-oxyacetic acid, 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl)uracil, thioguanine, and 2,6-diaminopurine. Nucleotide sequences typically carry genetic information, including information used by cellular machinery to make proteins and enzymes.These terms include double- or single-stranded genomic and cDNA, RNA, any synthetic and genetically engineered polynucleotide, and both sense and antisense polynucleotides. This includes single- and double-stranded molecules, i.e., DNA-DNA, DNA-RNA, and RNA-RNA hybrids, as well as "protein nucleic acids" (PNAs) formed by conjugating bases to an amino acid backbone. This also includes nucleic acids containing carbohydrates or lipids. Exemplary DNAs include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA. Exemplary RNAs include single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursor messenger RNA (pre-mRNA), short or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterologous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozymes, flexizymes, small nucleolar RNA (snoRNA), spliced ​​leader RNA, viral RNA, and viral satellite RNA.

[0077] The polynucleotides described herein can be synthesized by standard methods known in the art, for example, by using an automated DNA synthesizer (such as those commercially available from Biosearch, Applied Biosystems, etc.). For example, phosphorothioate oligonucleotides can be prepared using controlled pore glass polymer supports (Stein et al., Nucl. Acids Res., 16, 3209, (1988)), and methylphosphonate oligonucleotides can be prepared using controlled pore glass polymer supports (Sarin et al., Proc. Natl. Acad. Sci. USA, 85, 7448-7451, (1988)). Several methods have been developed for delivering antisense DNA or RNA to cells; for example, antisense molecules can be injected directly into tissue sites, or modified antisense molecules designed to target desired cells (antisense linked to peptides or antibodies that specifically bind to receptors or antigens expressed on the surface of target cells) can be administered systemically. Alternatively, RNA molecules can be generated by in vitro and in vivo transcription of DNA sequences encoding antisense RNA molecules. Such DNA sequences may be incorporated into a wide variety of vectors incorporating an appropriate RNA polymerase promoter (e.g., T7 or SP6 polymerase promoter). Alternatively, antisense cDNA constructs that synthesize antisense RNA constitutively or inducibly, depending on the promoter used, can be stably introduced into cell lines. However, achieving intracellular concentrations of antisense sufficient to suppress translation of endogenous mRNA is often difficult. Therefore, a preferred approach utilizes recombinant DNA constructs in which antisense oligonucleotides are placed under the control of a strong promoter. Use of such constructs to transfect target cells in patients results in the transcription of sufficient amounts of single-stranded RNA that forms complementary base pairs with endogenous target gene transcripts, thereby preventing translation of the target gene mRNA. For example, vectors can be introduced in vivo so that they are taken up by cells and direct the transcription of antisense RNA.As long as such vector can be transcribed to produce the desired antisense RNA, it can remain episomal or be integrated into chromosome.Such vector can be constructed by recombinant DNA technology methods standard in the art.Vector can be plasmid, virus, or other known in the art, used for replication and expression in mammalian cells.The expression of the sequence encoding antisense RNA can be by any promoter known in the art to function in mammalian cells, preferably human cells.Such promoter can be inducible or constitutive.Any type of plasmid, cosmid, yeast artificial chromosome, or viral vector can be used to prepare recombinant DNA constructs that can be directly introduced into tissue sites.

[0078] Polynucleotides may be adjacent to natural regulatory (expression control) sequences or may be associated with heterologous sequences, including promoters, internal ribosome entry sites (IRES) and other ribosome binding site sequences, enhancers, response elements, suppressors, signal sequences, polyadenylation sequences, introns, 5'- and 3'-non-coding regions, and the like. Nucleic acids may also be modified by many means known in the art. Non-limiting examples of such modifications include methylation, "caps," substitution of one or more naturally occurring nucleotides with an analog, and internucleotide modifications (e.g., internucleotide modifications having uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoramidates, carbamates, etc.) and charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.)). Polynucleotides may contain one or more additional covalently linked moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g., metals, radioactive metals, iron, metal oxides, etc.), and alkylating agents. Polynucleotides may be derivatized by formation of a methyl or ethyl phosphotriester or alkyl phosphoramidate linkage. Furthermore, the polynucleotides herein may also be modified with a label capable of providing a detectable signal, either directly or indirectly. Exemplary labels include radioisotopes, fluorescent molecules, isotopes (e.g., radioisotopes), biotin, etc.

[0079] A "protein," "peptide," or "polypeptide" includes a polymer of amino acid residues linked together by peptide bonds. The term refers to proteins, polypeptides, and peptides of any size, structure, or function. Typically, a protein is at least three amino acids long. A protein may refer to an individual protein or a collection of proteins. Proteins of the present invention preferably contain only naturally occurring amino acids, although unnatural amino acids (i.e., compounds that do not occur in nature but can be incorporated into polypeptide chains) and / or amino acid analogs known in the art may alternatively be used. One or more amino acids in a protein may also be modified by the addition of chemical entities such as, for example, carbohydrate groups, hydroxyl groups, phosphate groups, farnesyl groups, isofarnesyl groups, fatty acid groups, linkers for conjugation or functionalization, or other modifications. A protein may also be a single molecule or a multimolecular complex. A protein may be a fragment of a naturally occurring protein or peptide. A protein may be naturally occurring, recombinant, synthetic, or any combination thereof.

[0080] Amino acid residues may be indicated by their corresponding single letter codes, for example, R (arginine), H (histidine), K (lysine), D (aspartic acid), E (glutamic acid), S (serine), T (threonine), N (asparagine), Q (glutamine), C (cysteine), G (glycine), P (proline), A (alanine), V (valine), I (isoleucine), L (leucine), M (methionine), F (phenylalanine), Y (tyrosine), W (tryptophan).

[0081] A "peptidase," "protease," or "proteinase" is an enzyme that catalyzes the hydrolysis of peptide bonds. Peptidases digest polypeptides into shorter fragments and can generally be classified as endopeptidases and exopeptidases, which cleave polypeptide chains internally and at the terminals, respectively. An exopeptidase according to the present application can be an "aminopeptidase" or a "carboxypeptidase," which cleaves a single amino acid from the amino or carboxy terminus, respectively. Peptidases (e.g., aminopeptidases) can also be referred to as "cutters" or "cleavage agents."

[0082] "TET aminopeptidase" is composed of 12 monomers assembled into a tetrahedron with three active sites at each corner. To access the active sites for digestion, the polypeptide must pass through a hole that leads to the central chamber of the tetrahedron. Each of the four faces of the tetrahedron contains a hole in the center of the face. The holes are narrow and do not allow larger compounds (e.g., double-stranded DNA) to pass through.

[0083] The term "avidin protein" refers to a biotin-binding protein, and generally has a biotin-binding site on each of the four subunits of the avidin protein. Avidin proteins include, for example, avidin, streptavidin, traptavidin, tamavidin, bladdervidin, zenavidin, and their homologs and variants. In some cases, avidin proteins in monomeric, dimeric, or tetrameric forms can be used. In some embodiments, the avidin protein of the avidin protein complex is streptavidin in tetrameric form (e.g., homotetramer).

[0084] The term "cut depth" or "cutting depth" refers to the degree to which amino acids are successively exposed at the end of a polypeptide during the degradation process that occurs during sequencing of the polypeptide. An increased cut depth indicates that more amino acids are successively exposed, and therefore, more of the polypeptide is sequenced. A decreased cut depth indicates that fewer amino acids are successively exposed, and therefore, less of the polypeptide is sequenced.

[0085] The term "percentage of reads that terminate at a particular residue" refers to the percentage of reads that terminate at the last recognizable position in the sequence of a polypeptide or at a preferred position that precedes the last recognizable position in the sequence of a polypeptide.

[0086] An increase in the percentage of reads that end at a particular residue indicates a greater proportion of the total number of reads that reach that particular residue. A decrease in the percentage of reads that end at a particular residue indicates a smaller proportion of the total number of reads that reach that particular residue.

[0087] The terms "cut rate," "cutting rate," "cut speed," or "cutting speed" refer to the rate at which amino acids are successively exposed at the termini of a polypeptide during the degradation process that occurs during sequencing of the polypeptide. The cleavage rate is calculated as 1 / t ROI where t ROI is the duration that a recognizable amino acid (i.e., a recognition segment or region of interest) is reversibly bound by a fluorescently labeled recognition agent. An increased cleavage rate indicates that amino acids are successively exposed more rapidly, and thus, polypeptide sequencing occurs more rapidly. A decreased cleavage rate indicates that amino acids are successively exposed more slowly, and thus, polypeptide sequencing occurs more slowly. The cleavage rate of a compound can be normalized to the cleavage rate of a control compound.

[0088] The term "click chemistry" refers to a chemical synthesis technique introduced by K. Barry Sharpless of The Scripps Research Institute, describing chemistry tailored to rapidly and reliably generate covalent bonds by linking together small units containing reactive groups. See, e.g., Kolb, Finn, and Sharpless, Angewandte Chemie International Edition (2001), 40:2004-2021; Evans, Australian Journal of Chemistry (2007), 60:384-395. Exemplary coupling reactions (some of which can be classified as "click chemistry") include, but are not limited to, the formation of esters, thioesters, and amides (e.g., peptide coupling) from activated acids or acyl halides; nucleophilic substitution reactions (e.g., nucleophilic displacement of halides or ring opening of strained ring systems); azide-alkyne Huisgen cycloadditions; thiol-yne additions; imine formation; Michael additions (e.g., maleimide additions); and Diels-Alder reactions (e.g., tetrazine [4 + 2] cycloadditions). Exemplary click chemistry reactions include, but are not limited to, azide-alkyne Huisgen cycloadditions and Diels-Alder reactions (e.g., tetrazine [4 + 2] cycloadditions). In some embodiments, click chemistry reactions are modular, broad in scope, give high chemical yields, generate harmless by-products, are stereospecific, exhibit large thermodynamic driving forces of >84 kJ / mol to promote reactions with a single reaction product, and / or can be performed under physiological conditions.In some embodiments, click chemistry reactions exhibit high atom economy, can be carried out under simple reaction conditions, use readily available starting materials and reagents, do not use toxic solvents or use benign or easily removed solvents (preferably water), and / or provide simple product isolation by non-chromatographic methods (crystallization or distillation).

[0089] As used herein, the term "click chemistry handle" refers to a reactant or reactive group that can participate in a click chemistry reaction. For example, a strained alkyne, such as cyclooctyne, is a click chemistry handle because it can participate in strain-promoted cycloaddition (see, e.g., Table 1). Generally, a click chemistry reaction requires at least two molecules containing click chemistry handles that can react with each other. Such pairs of click chemistry handles that react with each other are sometimes referred to herein as partner click chemistry handles. For example, azide is a partner click chemistry handle to cyclooctyne or other alkynes. Exemplary click chemistry handles suitable for use with some embodiments of the present invention are described herein, e.g., in Tables 1 and 2. In some embodiments, click chemistry handles that can react to form a covalent bond in the presence of a metal catalyst, e.g., copper(II), are used. In some embodiments, click chemistry handles that can react to form a covalent bond in the absence of a metal catalyst are used. Further suitable click chemistry handles will be known to those skilled in the art and include, but are not limited to, the click chemistry reaction partners, groups and handles described in, for example, Becer, Hoogenboom and Schubert, Click Chemistry beyond Metal-Catalyzed Cycloaddition, Angewandte Chemie International Edition (2009) 48:4900-4908 and PCT / US2012 / 044584 (these references are incorporated herein by reference for their discussion of click chemistry handles and methodologies).

[0090] [Table 1]

[0091] [Table 2]

[0092] Detailed Description of the Invention The embodiments described herein are not limited to specific embodiments, systems, compositions, methods, or configurations, as such may, of course, vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, unless specifically defined herein.

[0093] Compound: In one embodiment, a compound of formula (I): LY(I) Provided herein is a compound of the formula: wherein L comprises a polypeptidyl group; and Y comprises an oligonucleotide, or a salt thereof.

[0094] In another embodiment, a compound of formula (II): ZLY(II) Provided herein is a compound of the formula: wherein L comprises a polypeptidyl group; Y comprises an oligonucleotide; and Z is a polypeptide, or a salt thereof.

[0095] In certain embodiments, a polypeptidyl group comprises at least 5 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 6 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 7 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 8 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 9 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 10 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 11 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 12 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 13 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 14 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 15 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 16 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 17 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 18 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 19 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 20 amino acid residues. In certain embodiments, a polypeptidyl group comprises 5 to 20 amino acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 5 to 18 amino acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 5 to 15 amino acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 7 to 13 amino acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 9 to 11 amino acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 7 to 20 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains between 9 and 20 amino acid residues (inclusive).In certain embodiments, the polypeptidyl group contains 11 to 20 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 7 to 18 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 9 to 18 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 11 to 18 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 7 to 15 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 8 to 15 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 9 to 15 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 9 to 14 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 9 to 13 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 9 to 12 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 10 to 15 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 10 to 14 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 10 to 13 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 10 to 12 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 11 to 15 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 11 to 14 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 11 to 13 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 11 to 12 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group comprises 5 amino acid residues. In certain embodiments, the polypeptidyl group comprises 6 amino acid residues. In certain embodiments, the polypeptidyl group comprises 7 amino acid residues. In certain embodiments, the polypeptidyl group comprises 8 amino acid residues. In certain embodiments, the polypeptidyl group comprises 9 amino acid residues.In certain embodiments, the polypeptidyl group contains 10 amino acid residues. In certain embodiments, the polypeptidyl group contains 11 amino acid residues. In certain embodiments, the polypeptidyl group contains 12 amino acid residues. In certain embodiments, the polypeptidyl group contains 13 amino acid residues. In certain embodiments, the polypeptidyl group is 14 amino acid residues. In certain embodiments, the polypeptidyl group contains 15 amino acid residues. In certain embodiments, the polypeptidyl group contains 16 amino acid residues. In certain embodiments, the polypeptidyl group contains 17 amino acid residues. In certain embodiments, the polypeptidyl group contains 18 amino acid residues. In certain embodiments, the polypeptidyl group contains 19 amino acid residues. In certain embodiments, the polypeptidyl group contains 20 amino acid residues.

[0096] In certain embodiments, a polypeptidyl group is at least about 20 Å in length. In certain embodiments, a polypeptidyl group is at least about 25 Å in length. In certain embodiments, a polypeptidyl group is at least about 30 Å in length. In certain embodiments, a polypeptidyl group is at least about 33 Å in length. In certain embodiments, a polypeptidyl group is at least about 35 Å in length. In certain embodiments, a polypeptidyl group is at least about 40 Å in length. In certain embodiments, a polypeptidyl group is at least about 45 Å in length. In certain embodiments, a polypeptidyl group is at least about 50 Å in length. In certain embodiments, a polypeptidyl group is at least about 55 Å in length. In certain embodiments, a polypeptidyl group is at least about 60 Å in length. In certain embodiments, a polypeptidyl group is at least about 65 Å in length. In certain embodiments, a polypeptidyl group is at least about 70 Å in length. In certain embodiments, the polypeptidyl group is at least about 75 Å in length. In certain embodiments, the polypeptidyl group is about 20 Å to about 75 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å to about 70 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å to about 65 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å to about 60 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å to about 55 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å to about 45 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å to about 40 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å to about 35 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 75 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 70 Å in length, inclusive.In certain embodiments, the polypeptidyl group is about 25 Å to about 65 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 60 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 55 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 45 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 40 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 35 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 75 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 70 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 65 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 60 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 55 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 45 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 40 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 35 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 20 Å in length. In certain embodiments, the polypeptidyl group is about 25 Å in length. In certain embodiments, the polypeptidyl group is about 30 Å in length. In certain embodiments, the polypeptidyl group is about 33 Å in length. In certain embodiments, the polypeptidyl group is about 35 Å in length. In certain embodiments, the polypeptidyl group is about 40 Å in length. In certain embodiments, the polypeptidyl group is about 45 Å in length. In certain embodiments, the polypeptidyl group is about 50 Å in length.In certain embodiments, the polypeptidyl group is about 55 Å in length. In certain embodiments, the polypeptidyl group is about 60 Å in length. In certain embodiments, the polypeptidyl group is about 65 Å in length. In certain embodiments, the polypeptidyl group is about 70 Å in length. In certain embodiments, the polypeptidyl group is about 75 Å in length.

[0097] In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive), and is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive), and is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive), and is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues and is about 25 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 11 amino acid residues and is about 25 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 12 amino acid residues and is about 25 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues, inclusive, and is about 25 Å to about 45 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues, inclusive, and is about 25 Å to about 45 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive), and is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues, and is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 11 amino acid residues, and is about 25 Å to about 45 Å in length (inclusive).In certain embodiments, the polypeptidyl group comprises 12 amino acid residues and is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive) and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive) and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive) and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues, and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 11 amino acid residues, and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 12 amino acid residues, and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive), and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive) and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive) and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive) and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues and is about 25 Å to about 35 Å in length (inclusive).In certain embodiments, the polypeptidyl group comprises 11 amino acid residues and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 12 amino acid residues and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive) and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive) and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive) and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues, and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 11 amino acid residues, and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 12 amino acid residues, and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive), and is about 33 Å in length. In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive), and is approximately 33 Å in length. In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive), and is approximately 33 Å in length. In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is approximately 33 Å in length. In certain embodiments, the polypeptidyl group comprises 10 amino acid residues, and is approximately 33 Å in length.In certain embodiments, the polypeptidyl group comprises 11 amino acid residues and is approximately 33 Å in length. In certain embodiments, the polypeptidyl group comprises 12 amino acid residues and is approximately 33 Å in length.

[0098] In certain embodiments, the polypeptidyl group comprises at least one negatively charged moiety at physiological pH. In certain embodiments, the polypeptidyl group comprises at least two negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least three negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least four negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least five negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least six negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least seven negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least eight negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least nine negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least 10 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 1 to 10 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 2 to 10 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 3 to 10 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 4 to 10 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 5 to 10 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 1 to 9 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group contains 2 to 9 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group contains 3 to 9 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group contains 4 to 9 (inclusive) negatively charged moieties at physiological pH.In certain embodiments, the polypeptidyl group comprises 5 to 9 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 1 to 8 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 2 to 8 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 3 to 8 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 4 to 8 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 5 to 8 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 1 to 7 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 2 to 7 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 3 to 7 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 4 to 7 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 5 to 7 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 1 to 6 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 2 to 6 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group contains 1 to 5 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group contains 2 to 5 (inclusive) negatively charged moieties at physiological pH.In certain embodiments, the polypeptidyl group comprises 3 to 5 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 4 to 5 (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 1 negatively charged moiety at physiological pH. In certain embodiments, the polypeptidyl group comprises 2 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 3 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 4 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 5 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 6 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 7 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 8 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 9 negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises 10 negatively charged moieties at physiological pH.

[0099] In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 30 Å to about 35 Å in length. In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 33 Å in length. In certain embodiments, the polypeptidyl group comprises 4 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 50 Å in length. In certain embodiments, the polypeptidyl group comprises 4 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 45 Å in length. In certain embodiments, the polypeptidyl group comprises 4 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 40 Å (inclusive) in length. In certain embodiments, the polypeptidyl group comprises 4 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 35 Å (inclusive) in length. In certain embodiments, the polypeptidyl group comprises 4 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 30 Å to about 35 Å (inclusive) in length.In certain embodiments, the polypeptidyl group comprises 4 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 33 Å in length. In certain embodiments, the polypeptidyl group comprises 5 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 50 Å in length. In certain embodiments, the polypeptidyl group comprises 5 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 45 Å in length. In certain embodiments, the polypeptidyl group comprises 5 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 40 Å in length. In certain embodiments, the polypeptidyl group comprises 5-6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 35 Å (inclusive) in length. In certain embodiments, the polypeptidyl group comprises 5-6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 30 Å to about 35 Å (inclusive) in length. In certain embodiments, the polypeptidyl group comprises 5-6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 33 Å in length.

[0100] In certain embodiments, a polypeptidyl group comprises at least one aspartic acid residue. In certain embodiments, a polypeptidyl group comprises at least two aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least three aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least four aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least five aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least six aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least seven aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least eight aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least nine aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least ten aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least eleven aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least 12 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least 13 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least 14 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises at least 15 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 1 to 15 aspartic acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 1 to 14 aspartic acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 1 to 13 aspartic acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 1 to 12 aspartic acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 1 to 11 aspartic acid residues (inclusive). In certain embodiments, the polypeptidyl group contains 1 to 10 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 2 to 10 (inclusive) aspartic acid residues.In certain embodiments, the polypeptidyl group contains 3 to 10 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 4 to 10 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 5 to 10 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 1 to 9 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 2 to 9 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 3 to 9 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 4 to 9 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 5 to 9 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 1 to 8 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 2 to 8 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 3 to 8 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 4 to 8 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 5 to 8 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 1 to 7 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 2 to 7 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 1 to 6 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 2 to 6 (inclusive) aspartic acid residues. In certain embodiments, the polypeptidyl group contains 3 to 6 (inclusive) aspartic acid residues.In certain embodiments, a polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 1 to 5 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 2 to 5 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 3 to 5 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 4 to 5 (inclusive) aspartic acid residues. In certain embodiments, a polypeptidyl group contains 1 aspartic acid residue. In certain embodiments, a polypeptidyl group contains 2 aspartic acid residues. In certain embodiments, a polypeptidyl group contains 3 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 4 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 5 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 6 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 7 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 8 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 9 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 10 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 11 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 12 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 13 aspartic acid residues. In certain embodiments, a polypeptidyl group comprises 14 aspartic acid residues. In certain embodiments, the polypeptidyl group comprises 15 aspartic acid residues.

[0101] In certain embodiments, a polypeptidyl group comprises at least one phenylalanine residue. In certain embodiments, a polypeptidyl group comprises at least two phenylalanine residues. In certain embodiments, a polypeptidyl group comprises at least three phenylalanine residues. In certain embodiments, a polypeptidyl group comprises at least four phenylalanine residues. In certain embodiments, a polypeptidyl group comprises at least five phenylalanine residues. In certain embodiments, a polypeptidyl group comprises at least six phenylalanine residues. In certain embodiments, a polypeptidyl group comprises at least seven phenylalanine residues. In certain embodiments, a polypeptidyl group comprises at least eight phenylalanine residues. In certain embodiments, a polypeptidyl group comprises at least nine phenylalanine residues. In certain embodiments, a polypeptidyl group comprises at least ten phenylalanine residues. In certain embodiments, a polypeptidyl group comprises between one and ten phenylalanine residues (inclusive). In certain embodiments, a polypeptidyl group contains 1 to 9 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 1 to 8 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 1 to 7 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 1 to 6 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 1 to 5 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 1 to 4 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 1 to 3 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 1 to 2 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 2 to 10 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains from 2 to 9 (inclusive) phenylalanine residues.In certain embodiments, a polypeptidyl group contains 2 to 8 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 2 to 7 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 2 to 6 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 2 to 5 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 2 to 4 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 2 to 3 (inclusive) phenylalanine residues. In certain embodiments, a polypeptidyl group contains 1 phenylalanine residue. In certain embodiments, a polypeptidyl group contains 2 phenylalanine residues. In certain embodiments, a polypeptidyl group contains 3 phenylalanine residues. In certain embodiments, a polypeptidyl group contains 4 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 6 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 7 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 8 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 9 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 10 phenylalanine residues.

[0102] In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) phenylalanine residues.In certain embodiments, the polypeptidyl group contains five aspartic acid residues and the polypeptidyl group contains one to three (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains six aspartic acid residues and the polypeptidyl group contains one to three (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains three to seven (inclusive) aspartic acid residues and the polypeptidyl group contains one to two (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains four to seven (inclusive) aspartic acid residues and the polypeptidyl group contains one to two (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains five to seven (inclusive) aspartic acid residues and the polypeptidyl group contains one to two (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and 1 to 2 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and 1 to 2 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and 1 to 2 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and 1 to 2 (inclusive) phenylalanine residues. In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and 1 phenylalanine residue. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains one phenylalanine residue, hi certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains one phenylalanine residue.In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains one phenylalanine residue. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains one phenylalanine residue. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains one phenylalanine residue. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and the polypeptidyl group contains one phenylalanine residue. In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains two phenylalanine residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 phenylalanine residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 2 phenylalanine residues. In certain embodiments, the polypeptidyl group comprises six aspartic acid residues and the polypeptidyl group comprises two phenylalanine residues.

[0103] In certain embodiments, a polypeptidyl group comprises at least one glycine residue. In certain embodiments, a polypeptidyl group comprises at least two glycine residues. In certain embodiments, a polypeptidyl group comprises at least three glycine residues. In certain embodiments, a polypeptidyl group comprises at least four glycine residues. In certain embodiments, a polypeptidyl group comprises at least five glycine residues. In certain embodiments, a polypeptidyl group comprises at least six glycine residues. In certain embodiments, a polypeptidyl group comprises at least seven glycine residues. In certain embodiments, a polypeptidyl group comprises at least eight glycine residues. In certain embodiments, a polypeptidyl group comprises at least nine glycine residues. In certain embodiments, a polypeptidyl group comprises at least ten glycine residues. In certain embodiments, a polypeptidyl group comprises between one and ten glycine residues (inclusive). In certain embodiments, a polypeptidyl group contains 1 to 9 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 1 to 8 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 1 to 7 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 1 to 6 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 1 to 5 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 1 to 4 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 1 to 3 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 1 to 2 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 2 to 10 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 2 to 9 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 2 to 8 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 2 to 7 (inclusive) glycine residues.In certain embodiments, a polypeptidyl group contains 2 to 6 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 2 to 5 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 2 to 4 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 2 to 3 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 3 to 10 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 3 to 9 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 3 to 8 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 3 to 7 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 3 to 6 (inclusive) glycine residues. In certain embodiments, a polypeptidyl group contains 3 to 5 glycine residues (inclusive). In certain embodiments, a polypeptidyl group contains 3 to 4 glycine residues (inclusive). In certain embodiments, a polypeptidyl group contains 1 glycine residue. In certain embodiments, a polypeptidyl group contains 2 glycine residues. In certain embodiments, a polypeptidyl group contains 3 glycine residues. In certain embodiments, a polypeptidyl group contains 4 glycine residues. In certain embodiments, a polypeptidyl group contains 5 glycine residues. In certain embodiments, a polypeptidyl group contains 6 glycine residues. In certain embodiments, a polypeptidyl group contains 7 glycine residues. In certain embodiments, a polypeptidyl group contains 8 glycine residues. In certain embodiments, a polypeptidyl group contains 9 glycine residues. In certain embodiments, a polypeptidyl group contains 10 glycine residues.

[0104] In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) glycine residues.In certain embodiments, the polypeptidyl group contains six aspartic acid residues and the polypeptidyl group contains one to three (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains three to seven (inclusive) aspartic acid residues and the polypeptidyl group contains two to three (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains four to seven (inclusive) aspartic acid residues and the polypeptidyl group contains two to three (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains five to seven (inclusive) aspartic acid residues and the polypeptidyl group contains two to three (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains four to six (inclusive) aspartic acid residues and the polypeptidyl group contains two to three (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 to 3 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 2 to 3 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and the polypeptidyl group contains 2 to 3 (inclusive) glycine residues. In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 glycine residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 glycine residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 glycine residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 glycine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 glycine residues.In certain embodiments, the polypeptidyl group comprises five aspartic acid residues and the polypeptidyl group comprises two glycine residues. In certain embodiments, the polypeptidyl group comprises six aspartic acid residues and the polypeptidyl group comprises two glycine residues. In certain embodiments, the polypeptidyl group comprises three to seven (inclusive) aspartic acid residues and the polypeptidyl group comprises three glycine residues. In certain embodiments, the polypeptidyl group comprises four to seven (inclusive) aspartic acid residues and the polypeptidyl group comprises three glycine residues. In certain embodiments, the polypeptidyl group comprises five to seven (inclusive) aspartic acid residues and the polypeptidyl group comprises three glycine residues. In certain embodiments, the polypeptidyl group comprises four to six (inclusive) aspartic acid residues and the polypeptidyl group comprises three glycine residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 3 glycine residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 3 glycine residues. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and the polypeptidyl group contains 3 glycine residues.

[0105] In certain embodiments, a polypeptidyl group comprises at least one proline residue. In certain embodiments, a polypeptidyl group comprises at least two proline residues. In certain embodiments, a polypeptidyl group comprises at least three proline residues. In certain embodiments, a polypeptidyl group comprises at least four proline residues. In certain embodiments, a polypeptidyl group comprises at least five proline residues. In certain embodiments, a polypeptidyl group comprises at least six proline residues. In certain embodiments, a polypeptidyl group comprises at least seven proline residues. In certain embodiments, a polypeptidyl group comprises at least eight proline residues. In certain embodiments, a polypeptidyl group comprises at least nine proline residues. In certain embodiments, a polypeptidyl group comprises at least ten proline residues. In certain embodiments, a polypeptidyl group comprises between one and ten (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 to 9 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 to 8 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 to 7 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 to 6 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 to 5 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 to 4 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 to 3 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 to 2 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 2 to 10 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 2 to 9 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 2 to 8 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 2 to 7 (inclusive) proline residues.In certain embodiments, a polypeptidyl group contains 2 to 6 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 2 to 5 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 2 to 4 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 2 to 3 (inclusive) proline residues. In certain embodiments, a polypeptidyl group contains 1 proline residue. In certain embodiments, a polypeptidyl group contains 2 proline residues. In certain embodiments, a polypeptidyl group contains 3 proline residues. In certain embodiments, a polypeptidyl group contains 4 proline residues. In certain embodiments, a polypeptidyl group contains 5 proline residues. In certain embodiments, a polypeptidyl group contains 6 proline residues. In certain embodiments, a polypeptidyl group contains 7 proline residues. In certain embodiments, the polypeptidyl group comprises 8 proline residues. In certain embodiments, the polypeptidyl group comprises 9 proline residues. In certain embodiments, the polypeptidyl group comprises 10 proline residues.

[0106] In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and the polypeptidyl group contains 1 to 4 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 1 to 3 (inclusive) proline residues.In certain embodiments, the polypeptidyl group contains six aspartic acid residues and the polypeptidyl group contains one to three (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains three to seven (inclusive) aspartic acid residues and the polypeptidyl group contains one to two (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains four to seven (inclusive) aspartic acid residues and the polypeptidyl group contains one to two (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains five to seven (inclusive) aspartic acid residues and the polypeptidyl group contains one to two (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains four to six (inclusive) aspartic acid residues and the polypeptidyl group contains one to two (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 to 2 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 1 to 2 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and the polypeptidyl group contains 1 to 2 (inclusive) proline residues. In certain embodiments, the polypeptidyl group contains 3 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 proline residue. In certain embodiments, the polypeptidyl group contains 4 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains 1 proline residue. In certain embodiments, the polypeptidyl group contains 5 to 7 (inclusive) aspartic acid residues and the polypeptidyl group contains one proline residue. In certain embodiments, the polypeptidyl group contains 4 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains one proline residue. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains one proline residue.In certain embodiments, the polypeptidyl group comprises five aspartic acid residues and the polypeptidyl group comprises one proline residue. In certain embodiments, the polypeptidyl group comprises six aspartic acid residues and the polypeptidyl group comprises one proline residue. In certain embodiments, the polypeptidyl group comprises three to seven (inclusive) aspartic acid residues and the polypeptidyl group comprises two proline residues. In certain embodiments, the polypeptidyl group comprises four to seven (inclusive) aspartic acid residues and the polypeptidyl group comprises two proline residues. In certain embodiments, the polypeptidyl group comprises five to seven (inclusive) aspartic acid residues and the polypeptidyl group comprises two proline residues. In certain embodiments, the polypeptidyl group comprises four to six (inclusive) aspartic acid residues and the polypeptidyl group comprises two proline residues. In certain embodiments, the polypeptidyl group contains 5 to 6 (inclusive) aspartic acid residues and the polypeptidyl group contains 2 proline residues. In certain embodiments, the polypeptidyl group contains 5 aspartic acid residues and the polypeptidyl group contains 2 proline residues. In certain embodiments, the polypeptidyl group contains 6 aspartic acid residues and the polypeptidyl group contains 2 proline residues.

[0107] In certain embodiments, a polypeptidyl group comprises at least one GP repeat. In certain embodiments, a polypeptidyl group comprises at least two GP repeats. In certain embodiments, a polypeptidyl group comprises at least three GP repeats. In certain embodiments, a polypeptidyl group comprises at least four GP repeats. In certain embodiments, a polypeptidyl group comprises at least five GP repeats. In certain embodiments, a polypeptidyl group comprises 1 to 5 (inclusive) GP repeats. In certain embodiments, a polypeptidyl group comprises 1 to 4 (inclusive) GP repeats. In certain embodiments, a polypeptidyl group comprises 1 to 3 (inclusive) GP repeats. In certain embodiments, a polypeptidyl group comprises 1 to 2 (inclusive) GP repeats. In certain embodiments, a polypeptidyl group comprises 1 GP repeat. In certain embodiments, a polypeptidyl group comprises 2 GP repeats. In certain embodiments, the polypeptidyl group comprises 3 GP repeats. In certain embodiments, the polypeptidyl group comprises 4 GP repeats. In certain embodiments, the polypeptidyl group comprises 5 GP repeats.

[0108] In certain embodiments, a polypeptidyl group comprises at least one GG repeat. In certain embodiments, a polypeptidyl group comprises at least two GG repeats. In certain embodiments, a polypeptidyl group comprises at least three GG repeats. In certain embodiments, a polypeptidyl group comprises at least four GG repeats. In certain embodiments, a polypeptidyl group comprises at least five GG repeats. In certain embodiments, a polypeptidyl group comprises 1 to 5 (inclusive) GG repeats. In certain embodiments, a polypeptidyl group comprises 1 to 4 (inclusive) GG repeats. In certain embodiments, a polypeptidyl group comprises 1 to 3 (inclusive) GG repeats. In certain embodiments, a polypeptidyl group comprises 1 to 2 (inclusive) GG repeats. In certain embodiments, a polypeptidyl group comprises 1 GG repeat. In certain embodiments, a polypeptidyl group comprises 2 GG repeats. In certain embodiments, the polypeptidyl group comprises 3 GG repeats. In certain embodiments, the polypeptidyl group comprises 4 GG repeats. In certain embodiments, the polypeptidyl group comprises 5 GG repeats.

[0109] In certain embodiments, a polypeptidyl group comprises at least one GGG repeat. In certain embodiments, a polypeptidyl group comprises at least two GGG repeats. In certain embodiments, a polypeptidyl group comprises at least three GGG repeats. In certain embodiments, a polypeptidyl group comprises at least four GGG repeats. In certain embodiments, a polypeptidyl group comprises at least five GGG repeats. In certain embodiments, a polypeptidyl group comprises 1 to 5 (inclusive) GGG repeats. In certain embodiments, a polypeptidyl group comprises 1 to 4 (inclusive) GGG repeats. In certain embodiments, a polypeptidyl group comprises 1 to 3 (inclusive) GGG repeats. In certain embodiments, a polypeptidyl group comprises 1 to 2 (inclusive) GGG repeats. In certain embodiments, a polypeptidyl group comprises 1 GGG repeat. In certain embodiments, a polypeptidyl group comprises 2 GGG repeats. In certain embodiments, the polypeptidyl group comprises 3 GGG repeats. In certain embodiments, the polypeptidyl group comprises 4 GGG repeats. In certain embodiments, the polypeptidyl group comprises 5 GGG repeats.

[0110] In certain embodiments, a polypeptidyl group comprises at least one DD repeat. In certain embodiments, a polypeptidyl group comprises at least two DD repeats. In certain embodiments, a polypeptidyl group comprises at least three DD repeats. In certain embodiments, a polypeptidyl group comprises at least four DD repeats. In certain embodiments, a polypeptidyl group comprises at least five DD repeats. In certain embodiments, a polypeptidyl group comprises from 1 to 5 (inclusive) DD repeats. In certain embodiments, a polypeptidyl group comprises from 1 to 4 (inclusive) DD repeats. In certain embodiments, a polypeptidyl group comprises from 1 to 3 (inclusive) DD repeats. In certain embodiments, a polypeptidyl group comprises from 1 to 2 (inclusive) DD repeats. In certain embodiments, a polypeptidyl group comprises one DD repeat. In certain embodiments, a polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises 3 DD repeats. In certain embodiments, the polypeptidyl group comprises 4 DD repeats. In certain embodiments, the polypeptidyl group comprises 5 DD repeats.

[0111] In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises two DD repeats.In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises three DD repeats.

[0112] In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises two DD repeats.In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises three DD repeats.

[0113] In certain embodiments, a polypeptidyl group comprises at least one DDD repeat. In certain embodiments, a polypeptidyl group comprises at least two DDD repeats. In certain embodiments, a polypeptidyl group comprises at least three DDD repeats. In certain embodiments, a polypeptidyl group comprises at least four DDD repeats. In certain embodiments, a polypeptidyl group comprises at least five DDD repeats. In certain embodiments, a polypeptidyl group comprises 1 to 5 (inclusive) DDD repeats. In certain embodiments, a polypeptidyl group comprises 1 to 4 (inclusive) DDD repeats. In certain embodiments, a polypeptidyl group comprises 1 to 3 (inclusive) DDD repeats. In certain embodiments, a polypeptidyl group comprises 1 to 2 (inclusive) DDD repeats. In certain embodiments, a polypeptidyl group comprises 1 DDD repeat. In certain embodiments, a polypeptidyl group comprises 2 DDD repeats. In certain embodiments, the polypeptidyl group comprises 3 DDD repeats. In certain embodiments, the polypeptidyl group comprises 4 DDD repeats. In certain embodiments, the polypeptidyl group comprises 5 DDD repeats.

[0114] In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two GG repeats (inclusive), and the polypeptidyl group comprises one to two DDD repeats (inclusive). In certain embodiments, the polypeptidyl group comprises one GG repeat, and the polypeptidyl group comprises one to two DDD repeats (inclusive). In certain embodiments, the polypeptidyl group comprises two GG repeats, and the polypeptidyl group comprises one to two DDD repeats (inclusive). In certain embodiments, the polypeptidyl group comprises one to three GG repeats (inclusive), and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one to two GG repeats (inclusive), and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one GG repeat, and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises two DDD repeats.In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises three DDD repeats.

[0115] In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises two DDD repeats.In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises three DDD repeats.

[0116] In certain embodiments, a polypeptidyl group comprises at least one FF repeat. In certain embodiments, a polypeptidyl group comprises at least two FF repeats. In certain embodiments, a polypeptidyl group comprises at least three FF repeats. In certain embodiments, a polypeptidyl group comprises at least four FF repeats. In certain embodiments, a polypeptidyl group comprises at least five FF repeats. In certain embodiments, a polypeptidyl group comprises 1 to 5 (inclusive) FF repeats. In certain embodiments, a polypeptidyl group comprises 1 to 4 (inclusive) FF repeats. In certain embodiments, a polypeptidyl group comprises 1 to 3 (inclusive) FF repeats. In certain embodiments, a polypeptidyl group comprises 1 to 2 (inclusive) FF repeats. In certain embodiments, a polypeptidyl group comprises 1 FF repeat. In certain embodiments, a polypeptidyl group comprises 2 FF repeats. In certain embodiments, the polypeptidyl group comprises 3 FF repeats. In certain embodiments, the polypeptidyl group comprises 4 FF repeats. In certain embodiments, the polypeptidyl group comprises 5 FF repeats.

[0117] In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats, and the polypeptidyl group comprises one to three (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats, and the polypeptidyl group comprises one to three (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat, and the polypeptidyl group comprises one to three (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises two GG repeats, and the polypeptidyl group comprises one to three (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats, and the polypeptidyl group comprises one to two (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one to two GG repeats (inclusive), and the polypeptidyl group comprises one to two FF repeats (inclusive). In certain embodiments, the polypeptidyl group comprises one GG repeat, and the polypeptidyl group comprises one to two FF repeats (inclusive). In certain embodiments, the polypeptidyl group comprises two GG repeats, and the polypeptidyl group comprises one to two FF repeats (inclusive). In certain embodiments, the polypeptidyl group comprises one to three GG repeats (inclusive), and the polypeptidyl group comprises one FF repeat. In certain embodiments, the polypeptidyl group comprises one to two GG repeats (inclusive), and the polypeptidyl group comprises one FF repeat. In certain embodiments, the polypeptidyl group comprises one GG repeat, and the polypeptidyl group comprises one FF repeat. In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises one FF repeat. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GG repeats and the polypeptidyl group comprises two FF repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GG repeats and the polypeptidyl group comprises two FF repeats. In certain embodiments, the polypeptidyl group comprises one GG repeat and the polypeptidyl group comprises two FF repeats.In certain embodiments, the polypeptidyl group comprises two GG repeats and the polypeptidyl group comprises two FF repeats.

[0118] In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats, and the polypeptidyl group comprises one to three (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats, and the polypeptidyl group comprises one to three (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat, and the polypeptidyl group comprises one to three (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises two GGG repeats, and the polypeptidyl group comprises one to three (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats, and the polypeptidyl group comprises one to two (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats, and the polypeptidyl group comprises one to two (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat, and the polypeptidyl group comprises one to two (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises two GGG repeats, and the polypeptidyl group comprises one to two (inclusive) FF repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats, and the polypeptidyl group comprises one FF repeat. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats, and the polypeptidyl group comprises one FF repeat. In certain embodiments, the polypeptidyl group comprises one GGG repeat, and the polypeptidyl group comprises one FF repeat. In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises one FF repeat. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) GGG repeats and the polypeptidyl group comprises two FF repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) GGG repeats and the polypeptidyl group comprises two FF repeats. In certain embodiments, the polypeptidyl group comprises one GGG repeat and the polypeptidyl group comprises two FF repeats.In certain embodiments, the polypeptidyl group comprises two GGG repeats and the polypeptidyl group comprises two FF repeats.

[0119] In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises one to three (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises one to two (inclusive) DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises one DD repeat. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises two DD repeats.In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises two DD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises three DD repeats. In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises three DD repeats.

[0120] In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises one to three (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises one to two (inclusive) DDD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises one DDD repeat. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises two DDD repeats.In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises two DDD repeats. In certain embodiments, the polypeptidyl group comprises one to three (inclusive) FF repeats and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises one to two (inclusive) FF repeats and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises one FF repeat and the polypeptidyl group comprises three DDD repeats. In certain embodiments, the polypeptidyl group comprises two FF repeats and the polypeptidyl group comprises three DDD repeats.

[0121] In certain embodiments, the oligonucleotide and polypeptide are at least 20 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 25 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 30 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 33 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 35 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 40 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 45 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 50 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 55 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 60 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 65 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 70 Å apart. In certain embodiments, the oligonucleotide and polypeptide are at least 75 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 20 Å to about 75 Å apart, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 20 Å to about 70 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 20 Å to about 65 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 20 Å to about 60 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 20 Å to about 55 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 20 Å to about 50 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 20 Å to about 45 Å, inclusive.In certain embodiments, the oligonucleotide and polypeptide are separated by about 20 Å to about 40 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 20 Å to about 35 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 75 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 70 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 65 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 60 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 55 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 50 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 45 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 40 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 25 Å to about 35 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 30 Å to about 75 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 30 Å to about 70 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 30 Å to about 65 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 30 Å to about 60 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 30 Å to about 55 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 30 Å to about 50 Å, inclusive. In certain embodiments, the oligonucleotide and polypeptide are separated by about 30 Å to about 45 Å, inclusive.In certain embodiments, the oligonucleotide and polypeptide are about 30 Å to about 40 Å apart, inclusive. In certain embodiments, the oligonucleotide and polypeptide are about 30 Å to about 35 Å apart, inclusive. In certain embodiments, the oligonucleotide and polypeptide are about 20 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 25 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 30 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 33 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 35 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 40 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 45 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 50 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 55 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 60 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 65 Å apart. In certain embodiments, the oligonucleotide and polypeptide are about 70 Å apart. In certain embodiments, the oligonucleotide and the polypeptide are separated by about 75 Å.

[0122] In certain embodiments, the polypeptidyl group is

[0123] [ka]

[0124] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0125] [ka]

[0126] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0127] [ka]

[0128] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0129] [ka]

[0130] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0131] [ka]

[0132] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0133] [ka]

[0134] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0135] [ka]

[0136] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0137] [ka]

[0138] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0139] [ka]

[0140] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0141] [ka]

[0142] or a salt thereof, and

[0143] [ka]

[0144] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0145] [ka]

[0146] or a salt thereof, and

[0147] [ka]

[0148] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0149] [ka]

[0150] or a salt thereof, and

[0151] [ka]

[0152] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0153] [ka]

[0154] or a salt thereof, and

[0155] [ka]

[0156] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0157] [ka]

[0158] or a salt thereof, and

[0159] [ka]

[0160] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0161] [ka]

[0162] or a salt thereof, and

[0163] [ka]

[0164] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0165] [ka]

[0166] or a salt thereof, and

[0167] [ka]

[0168] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0169] [ka]

[0170] or a salt thereof, and

[0171] [ka]

[0172] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0173] [ka]

[0174] or a salt thereof, and

[0175] [ka]

[0176] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0177] [ka]

[0178] or a salt thereof, and

[0179] [ka]

[0180] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0181] [ka]

[0182] or a salt thereof, and

[0183] [ka]

[0184] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0185] [ka]

[0186] or a salt thereof, and

[0187] [ka]

[0188] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0189] [ka]

[0190] or a salt thereof, and

[0191] [ka]

[0192] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0193] [ka]

[0194] or a salt thereof, and

[0195] [ka]

[0196] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0197] [ka]

[0198] or a salt thereof, and

[0199] [ka]

[0200] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0201] [ka]

[0202] or a salt thereof, and

[0203] [ka]

[0204] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0205] [ka]

[0206] or a salt thereof, and

[0207] [ka]

[0208] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0209] [ka]

[0210] or a salt thereof, and

[0211] [ka]

[0212] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0213] [ka]

[0214] or a salt thereof, and

[0215] [ka]

[0216] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0217] [ka]

[0218] or a salt thereof, and

[0219] [ka]

[0220] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0221] [ka]

[0222] or a salt thereof, and

[0223] [ka]

[0224] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0225] [ka]

[0226] or a salt thereof, and

[0227] [ka]

[0228] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0229] [ka]

[0230] or a salt thereof, and

[0231] [ka]

[0232] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0233] [ka]

[0234] or a salt thereof, and

[0235] [ka]

[0236] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0237] [ka]

[0238] or a salt thereof, and

[0239] [ka]

[0240] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0241] [ka]

[0242] or a salt thereof, and

[0243] [ka]

[0244] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0245] [ka]

[0246] or a salt thereof, and

[0247] [ka]

[0248] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0249] [ka]

[0250] or a salt thereof, and

[0251] [ka]

[0252] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0253] [ka]

[0254] or a salt thereof, and

[0255] [ka]

[0256] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0257] [ka]

[0258] or a salt thereof, and

[0259] [ka]

[0260] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0261] [ka]

[0262] or a salt thereof, and

[0263] [ka]

[0264] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0265] [ka]

[0266] or a salt thereof, and

[0267] [ka]

[0268] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0269] [ka]

[0270] or a salt thereof, and

[0271] [ka]

[0272] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0273] [ka]

[0274] or a salt thereof, and

[0275] [ka]

[0276] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0277] [ka]

[0278] or a salt thereof, and

[0279] [ka]

[0280] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0281] [ka]

[0282] or a salt thereof, and

[0283] [ka]

[0284] or a salt thereof. In certain embodiments, the polypeptidyl group is

[0285] [ka]

[0286] or a salt thereof. In certain embodiments, the polypeptidyl group has the formula

[0287] [ka]

[0288] or a salt thereof. In certain embodiments, the polypeptidyl group has the formula

[0289] [ka]

[0290] or a salt thereof. In certain embodiments, the polypeptidyl group has the formula

[0291] [ka]

[0292] or a salt thereof. In certain embodiments, the polypeptidyl group has the formula

[0293] [ka]

[0294] or a salt thereof. In certain embodiments, the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO:61), isoEGWRW (SEQ ID NO:62), DDGGGDDDFF (SEQ ID NO:32), GGSSSGSGNDEEFQ (SEQ ID NO:59), GGGGGDPDPD (SEQ ID NO:54), GGGGGDPDPDFF (SEQ ID NO:55), GGGGGGDPDPD (SEQ ID NO:57), GDGDGDGDGDFF (SEQ ID NO:53), GDDGDGDGDFF (SEQ ID NO:51), NNGGGNNNFF (SEQ ID NO:65), or DDGGGCyCyCyFF (SEQ ID NO:45), or a salt thereof, where Cy is cysteic acid. In certain embodiments, the polypeptide group comprises the sequence GPPPPPPPPG (SEQ ID NO:61), or a salt thereof. In certain embodiments, the polypeptidyl group comprises the sequence isoEGWRW (SEQ ID NO:62), or a salt thereof. In certain embodiments, a polypeptidyl group comprises the sequence DDGGGDDDFF (SEQ ID NO: 32), or a salt thereof. In certain embodiments, a polypeptidyl group comprises the sequence GGSSSGSGNDEEFQ (SEQ ID NO: 59), or a salt thereof. In certain embodiments, a polypeptidyl group comprises the sequence GGGGGDPDPD (SEQ ID NO: 54), or a salt thereof. In certain embodiments, a polypeptidyl group comprises the sequence GGGGGDPDPDFF (SEQ ID NO: 55), or a salt thereof. In certain embodiments, a polypeptidyl group comprises the sequence GGGGGGDPDPD (SEQ ID NO: 57), or a salt thereof. In certain embodiments, a polypeptidyl group comprises the sequence GDGDGDGDGDFF (SEQ ID NO: 53), or a salt thereof. In certain embodiments, a polypeptidyl group comprises the sequence GDDGDGDGDFF (SEQ ID NO: 51), or a salt thereof. In certain embodiments, a polypeptidyl group comprises the sequence NNGGGNNNFF (SEQ ID NO: 65), or a salt thereof. In certain embodiments, the polypeptidyl group comprises the sequence DDGGGCyCyCyFF (SEQ ID NO: 45) or a salt thereof, where Cy is cysteic acid.In certain embodiments, the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO:61), isoEGWRW (SEQ ID NO:62), DDGGGDDDFF (SEQ ID NO:32), GGSSSGSGNDEEFQ (SEQ ID NO:59), GGGGGDPDPD (SEQ ID NO:54), GGGGGDPDPDFF (SEQ ID NO:55), GGGGGGDPDPD (SEQ ID NO:57), GDGDGDGDGDFF (SEQ ID NO:53), GDDGDGDGDFF (SEQ ID NO:51), NNGGGNNNFF (SEQ ID NO:65), or DDGGGCyCyCyFF (SEQ ID NO:45), where Cy is cysteic acid. In certain embodiments, the polypeptidyl group comprises the sequence GPPPPPPPPG (SEQ ID NO:61). In certain embodiments, the polypeptidyl group comprises the sequence isoEGWRW (SEQ ID NO:62). In certain embodiments, the polypeptidyl group comprises the sequence DDGGGDDDFF (SEQ ID NO: 32). In certain embodiments, the polypeptidyl group comprises the sequence GGSSSGSGNDEEFQ (SEQ ID NO: 59). In certain embodiments, the polypeptidyl group comprises the sequence GGGGGDPDPD (SEQ ID NO: 54). In certain embodiments, the polypeptidyl group comprises the sequence GGGGGDPDPDFF (SEQ ID NO: 55). In certain embodiments, the polypeptidyl group comprises the sequence GGGGGGDPDPD (SEQ ID NO: 57). In certain embodiments, the polypeptidyl group comprises the sequence GDGDGDGDGDFF (SEQ ID NO: 53). In certain embodiments, the polypeptidyl group comprises the sequence GDDGDGDGDFF (SEQ ID NO: 51). In certain embodiments, the polypeptidyl group comprises the sequence NNGGGNNNFF (SEQ ID NO: 65). In one embodiment, the polypeptidyl group comprises the sequence DDGGGCyCyCyFF (SEQ ID NO: 45), where Cy is cysteic acid.

[0295] In certain embodiments, L further comprises at least one of an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted heteroalkylene, an optionally substituted heteroalkenylene, an optionally substituted heteroalkynylene, an optionally substituted heterocyclylene, an optionally substituted carbocyclylene, an optionally substituted arylene, an optionally substituted heteroarylene, a peptidyl group, a dipeptidyl group, a polypeptidyl group, a click chemistry handle, or a combination thereof.

[0296] In certain embodiments, L further comprises an optionally substituted alkylene. In certain embodiments, L further comprises an optionally substituted C 1-12 In certain embodiments, L is an optionally substituted C 1-10 In certain embodiments, L is an optionally substituted C 1-6 In certain embodiments, L is an unsubstituted C 1-6 In certain embodiments, L is a substituted C 1-6 In certain embodiments, L is a substituted C substituted with one or more oxo groups. 1-6 In certain embodiments, L is a substituted C alkylene group substituted with one oxo group. 1-6 In certain embodiments, L is a substituted C substituted with two oxo groups. 1-6In certain embodiments, L further comprises substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted n-propylene, substituted or unsubstituted isopropylene, substituted or unsubstituted n-butylene, substituted or unsubstituted tert-butylene, substituted or unsubstituted sec-butylene, substituted or unsubstituted isobutylene, substituted or unsubstituted n-pentylene, substituted or unsubstituted 3-pentanylene, substituted or unsubstituted amylene, substituted or unsubstituted neopentylene, substituted or unsubstituted 3-methylene-2-butanylene, substituted or unsubstituted tert-amylene, or substituted or unsubstituted n-hexylene. In certain embodiments, L further comprises unsubstituted methylene. In certain embodiments, L further comprises substituted methylene. In certain embodiments, L further comprises unsubstituted n-butylene. In certain embodiments, L further comprises substituted n-butylene. In certain embodiments, L further comprises a substituted n-butylene substituted with one or more oxo groups. In certain embodiments, L further comprises a substituted n-butylene substituted with one oxo group. In certain embodiments, L further comprises a substituted n-butylene substituted with two oxo groups. In certain embodiments, L is

[0297] [ka]

[0298] In certain embodiments, L further comprises optionally substituted alkenylene. In certain embodiments, L further comprises optionally substituted C 2-12 In certain embodiments, L is optionally substituted C 2-6In certain embodiments, L further comprises substituted or unsubstituted ethenylene, substituted or unsubstituted 1-propenylene, substituted or unsubstituted 2-propenylene, substituted or unsubstituted 1-butenylene, substituted or unsubstituted 2-butenylene, substituted or unsubstituted butadienylene, substituted or unsubstituted pentenylene, substituted or unsubstituted pentadienylene, or substituted or unsubstituted hexenylene. In certain embodiments, L further comprises optionally substituted alkynylene. In certain embodiments, L further comprises optionally substituted C 2-12 In certain embodiments, L is optionally substituted C 2-6 In certain embodiments, L further comprises substituted or unsubstituted ethynylene, substituted or unsubstituted 1-propynylene, substituted or unsubstituted 2-propynylene, substituted or unsubstituted 1-butynylene, substituted or unsubstituted 2-butynylene, substituted or unsubstituted pentynylene, or substituted or unsubstituted hexynylene. In certain embodiments, L further comprises optionally substituted heteroalkylene. In certain embodiments, L further comprises optionally substituted heteroC 1-12 In certain embodiments, L is an optionally substituted heterocyclic group. 1-6 In certain embodiments, L further comprises an optionally substituted heteroalkenylene. In certain embodiments, L further comprises an optionally substituted heteroC 1-12 In certain embodiments, L is an optionally substituted heterocyclic group. 1-6 In certain embodiments, L further comprises an optionally substituted heteroalkynylene. In certain embodiments, L further comprises an optionally substituted heteroalkynylene. In certain embodiments, L further comprises an optionally substituted heteroC 1-12 In certain embodiments, L is an optionally substituted heterocyclic group. 1-6 In certain embodiments, L further comprises an optionally substituted carbocyclylene. In certain embodiments, L further comprises an optionally substituted C 3-14In certain embodiments, L further comprises an optionally substituted heterocyclylene. In certain embodiments, L further comprises an optionally substituted 5- to 10-membered heterocyclylene. In certain embodiments, L further comprises an optionally substituted arylene. In certain embodiments, L further comprises an optionally substituted 6- to 14-membered arylene. In certain embodiments, L further comprises an optionally substituted phenylene. In certain embodiments, L further comprises substituted phenylene. In certain embodiments, L further comprises unsubstituted phenylene. In certain embodiments, L further comprises an optionally substituted heteroarylene. In certain embodiments, L further comprises an optionally substituted 5- to 14-membered heteroarylene. In certain embodiments, L further comprises an optionally substituted monocyclic heteroarylene. In certain embodiments, L further comprises an optionally substituted 5- to 6-membered monocyclic heteroarylene. In certain embodiments, L further comprises optionally substituted pyrrolylene, optionally substituted furanylene, optionally substituted thiophenylene, optionally substituted imidazolylene, optionally substituted pyrazolylene, optionally substituted oxazolylene, optionally substituted isoxazolylene, optionally substituted thiazolylene, optionally substituted isothiazolylene, optionally substituted triazolylene, optionally substituted oxadiazolylene, optionally substituted thiadiazolylene, or optionally substituted tetrazolylene. In certain embodiments, L further comprises optionally substituted pyridinylene, optionally substituted pyridazinylene, optionally substituted pyrimidinylene, optionally substituted pyrazinylene, optionally substituted triazinylene, optionally substituted tetrazinylene, optionally substituted oxepinylene, or optionally substituted thiepinylene. In certain embodiments, L further comprises an optionally substituted bicyclic heteroarylene (e.g., an optionally substituted bicyclic 9- or 10-membered heteroarylene in which 1, 2, 3, or 4 atoms in the heteroarylene ring system are independently oxygen, nitrogen, or sulfur). In certain embodiments, L further comprises an optionally substituted triazolylene.In certain embodiments, L is halogen, optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, -CN, -OR. A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A , -S(=O)SR A , -S(=O)N(R A )2, -S(=O)2R A , -S(=O)2OR A , -S(=O)2SR A , -S(=O)2N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)SR A , -OC(=O)N(R A )2, -OC(=NR A )R A , -OC(=NR A ) OR A , -OC(=NR A )SR A , -OC(=NR A )N(R A )2, -OS(=O)R A , -OS(=O)OR A , -OS(=O)SRA 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR A S(=O)2OR A 、-NR AS(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, and / or -B(OR A In certain embodiments, L is optionally substituted with one or more of the following groups:

[0299] [ka]

[0300] or a salt thereof. In certain embodiments, L is

[0301] [ka]

[0302] or a salt thereof. In certain embodiments, L further comprises a peptidyl group. In certain embodiments, L further comprises a dipeptidyl group. In certain embodiments, L further comprises a polypeptidyl group.

[0303] In certain embodiments, L further comprises a click chemistry handle. In certain embodiments, the click chemistry handle comprises an alkene. In certain embodiments, the click chemistry handle comprises a diene. In certain embodiments, the click chemistry handle comprises a dienophile. In certain embodiments, the click chemistry handle comprises a thiol. In certain embodiments, the click chemistry handle comprises a nitrile oxide. In certain embodiments, the click chemistry handle comprises a tetrazine. In certain embodiments, the click chemistry handle comprises an alkyne. In certain embodiments, the click chemistry handle comprises a terminal alkyne. In certain embodiments, the click chemistry handle comprises a strained alkyne. In certain embodiments, the click chemistry handle comprises an optionally substituted cyclooctyne. In certain embodiments, the click chemistry handle comprises a substituted cyclooctyne. In some embodiments, the click chemistry handle can react to form a covalent bond in the presence of a metal catalyst (e.g., copper(II)). In some embodiments, the click chemistry handle comprises a strained alkyne, which can react to form a covalent bond in the presence of a metal catalyst (e.g., copper(II)). In some embodiments, the click chemistry handle comprises an optionally substituted cyclooctyne, which can react to form a covalent bond in the presence of a metal catalyst (e.g., copper(II)). In some embodiments, the click chemistry handle comprises a substituted cyclooctyne, which can react to form a covalent bond in the presence of a metal catalyst (e.g., copper(II)). In some embodiments, the click chemistry handle can react to form a covalent bond in the absence of a metal catalyst. In some embodiments, the click chemistry handle comprises a strained alkyne, which can react to form a covalent bond in the absence of a metal catalyst. In some embodiments, the click chemistry handle comprises an optionally substituted cyclooctyne, which can react to form a covalent bond in the absence of a metal catalyst.In some embodiments, the click chemistry handle comprises a substituted cyclooctyne, which can react to form a covalent bond in the absence of a metal catalyst. In certain embodiments, the click chemistry handle comprises dibenzoazacyclooctyne (DIBAC or DBCO), biarylazacyclooctynone (BARAC), dibenzocyclooctyne (DIBO), difluorinated cyclooctyne (DIFO), bicyclononyne (BCN), dimethoxyazacyclooctyne (DIMAC), monofluorinated cyclooctyne (MOFO), cyclooctyne (OCT), and / or aryl-less cyclooctyne (ALO).

[0304] In certain embodiments, the click chemistry handle has formula (IV) or formula (V):

[0305] [ka]

[0306] or

[0307] [ka]

[0308] or a salt thereof, wherein: R 1 Each instance of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SRA 、-C(=O)N(R A )2、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )SR A 、-C(=NR A )N(R A )2、-S(=O)R A 、-S(=O)OR A 、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NRA )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR A S(=O)2OR A 、-NR A S(=O)2SR A 、-NR A S(=O)2N(R A )2、-Si(R A )3、-Si(R A )2OR A 、-Si(R A )(OR A )2、-Si(OR A )3、-OSi(R A )3、-OSi(R A )2OR A 、-OSi(R A )(OR A )2、-OSi(OR A )3、または-B(OR A )2、であり; R A each occurrence is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or R A two occurrences of are joined together with the intervening atoms to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; and Q is CH or N.

[0309] In certain embodiments, R 1 Each instance of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NRA C(=NR A )R A , -NR A C(=NR A ) OR A , -NR A C(=NR A )SR A , -NR A C(=NR A )N(R A )2, -NR A S(=O)R A , -NR A S(=O)OR A , -NR A S(=O)SR A , -NR A S(=O)N(R A )2, -NR A S(=O)2R A , -NR A S(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2. In certain embodiments, R 1 At least one example of is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SRA 、-SSR A 、-N3、-NO、-N(R A )2、-NO2、-C(=O)R A 、-C(=O)OR A 、-C(=O)SR A 、-C(=O)N(R A )2、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )SR A 、-C(=NR A )N(R A )2、-S(=O)R A 、-S(=O)OR A 、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SRA 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR A S(=O)2OR A 、-NR A S(=O)2SR A 、-NR A S(=O)2N(R A )2、-Si(R A )3、-Si(R A )2OR A 、-Si(R A )(OR A )2、-Si(OR A )3、-OSi(R A )3、-OSi(RA )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2.

[0310] In certain embodiments, R 1 At least one instance of R is hydrogen. 1 At least two instances of R are hydrogen. 1 At least three instances of R are hydrogen. 1 At least four instances of R are hydrogen. 1 At least five instances of R are hydrogen. 1 At least six instances of R are hydrogen. 1 At least seven instances of R are hydrogen. 1 At least 8 instances of R are hydrogen. 1 All examples of are hydrogen.

[0311] In certain embodiments, R A each occurrence is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or R A two occurrences of are joined together through the intervening atoms to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring. Aat least one occurrence of is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or R A and two occurrences of R are joined together with the intervening atoms to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring. In certain embodiments, at least one R A is hydrogen.

[0312] In certain embodiments, Q is CH. In certain embodiments, Q is N. In certain embodiments, R 1 At least one instance of is hydrogen and Q is CH. In certain embodiments, R 1 At least one instance of is hydrogen and Q is N. In certain embodiments, R 1 All instances of are hydrogen and Q is CH. In certain embodiments, R 1 All examples of are hydrogen and Q is N.

[0313] In certain embodiments, the click chemistry handle has the formula

[0314] [ka]

[0315] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0316] [ka]

[0317] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0318] [ka]

[0319] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0320] [ka]

[0321] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0322] [ka]

[0323] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0324] [ka]

[0325] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0326] [ka]

[0327] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0328] [ka]

[0329] or a salt thereof. In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and an optionally substituted alkylene. In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and an optionally substituted C 1-12 In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and optionally substituted C 1-10 In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and optionally substituted C 1-6 In certain embodiments, L is a group selected from the group consisting of a click chemistry handle of formula (IV) or formula (V) and an unsubstituted C 1-6 In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and a substituted C 1-6 In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and a substituted C substituted with one or more oxo groups. 1-6 In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and a substituted C substituted with one oxo group. 1-6 In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and a substituted C substituted with two oxo groups. 1-6and alkylene. In certain embodiments, L comprises a click chemistry handle of Formula (IV) or Formula (V) and substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted n-propylene, substituted or unsubstituted isopropylene, substituted or unsubstituted n-butylene, substituted or unsubstituted tert-butylene, substituted or unsubstituted sec-butylene, substituted or unsubstituted isobutylene, substituted or unsubstituted n-pentylene, substituted or unsubstituted 3-pentanylene, substituted or unsubstituted amylene, substituted or unsubstituted neopentylene, substituted or unsubstituted 3-methylene-2-butanylene, substituted or unsubstituted tert-amylene, or substituted or unsubstituted n-hexylene. In certain embodiments, L comprises a click chemistry handle of Formula (IV) or Formula (V) and unsubstituted methylene. In certain embodiments, L comprises a click chemistry handle of Formula (IV) or Formula (V) and substituted methylene. In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and unsubstituted n-butylene. In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and substituted n-butylene. In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and substituted n-butylene substituted with one or more oxo groups. In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and substituted n-butylene substituted with one oxo group. In certain embodiments, L comprises a click chemistry handle of formula (IV) or formula (V) and substituted n-butylene substituted with two oxo groups. In certain embodiments, L is

[0330] [ka]

[0331] or a salt thereof. In certain embodiments, L is

[0332] [ka]

[0333] or a salt thereof. In certain embodiments, L is

[0334] [ka]

[0335] or a salt thereof. In certain embodiments, L is

[0336] [ka]

[0337] or a salt thereof, and

[0338] [ka]

[0339] or a salt thereof. In certain embodiments, L is

[0340] [ka]

[0341] or a salt thereof, and

[0342] [ka]

[0343] or a salt thereof. In certain embodiments, L is

[0344] [ka]

[0345] or a salt thereof, and

[0346] [ka]

[0347] or a salt thereof. In certain embodiments, L is

[0348] [ka]

[0349] or a salt thereof, and

[0350] [ka]

[0351] or a salt thereof. In certain embodiments, L is

[0352] [ka]

[0353] or a salt thereof, and

[0354] [ka]

[0355] or a salt thereof. In certain embodiments, L is

[0356] [ka]

[0357] or a salt thereof,

[0358] [ka]

[0359] or a salt thereof, and

[0360] [ka]

[0361] or a salt thereof. In certain embodiments, L is

[0362] [ka]

[0363] or a salt thereof,

[0364] [ka]

[0365] or a salt thereof, and

[0366] [ka]

[0367] or a salt thereof. In certain embodiments, L is

[0368] [ka]

[0369] or a salt thereof, and

[0370] [ka]

[0371] or a salt thereof. In certain embodiments, L is

[0372] [ka]

[0373] or a salt thereof, and

[0374] [ka]

[0375] or a salt thereof. In certain embodiments, L is

[0376] [ka]

[0377] or a salt thereof, and

[0378] [ka]

[0379] or a salt thereof. In certain embodiments, L is

[0380] [ka]

[0381] or a salt thereof,

[0382] [ka]

[0383] or a salt thereof, and

[0384] [ka]

[0385] or a salt thereof. In certain embodiments, L is

[0386] [ka]

[0387] or a salt thereof,

[0388] [ka]

[0389] or a salt thereof, and

[0390] [ka]

[0391] or a salt thereof. In certain embodiments, L is

[0392] [ka]

[0393] or a salt thereof. In certain embodiments, L is

[0394] [ka]

[0395] or a salt thereof. In certain embodiments, L is

[0396] [ka]

[0397] or a salt thereof. In certain embodiments, L is

[0398] [ka]

[0399] or a salt thereof. In certain embodiments, L is

[0400] [ka]

[0401] or a salt thereof. In certain embodiments, L is

[0402] [ka]

[0403] or a salt thereof. In certain embodiments, L is

[0404] [ka]

[0405] or a salt thereof. In certain embodiments, L is

[0406] [ka]

[0407] or a salt thereof. In certain embodiments, L is

[0408] [ka]

[0409] or a salt thereof. In certain embodiments, L is

[0410] [ka]

[0411] or a salt thereof. In certain embodiments, the click chemistry handle has formula (VI):

[0412] [ka]

[0413] or a salt thereof, wherein: R 2 Each instance of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A)N(R A )2、-S(=O)R A 、-S(=O)OR A 、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SRA , -NR A C(=O)N(R A )2, -NR A C(=NR A )R A , -NR A C(=NR A ) OR A , -NR A C(=NR A )SR A , -NR A C(=NR A )N(R A )2, -NR A S(=O)R A , -NR A S(=O)OR A , -NR A S(=O)SR A , -NR A S(=O)N(R A )2, -NR A S(=O)2R A , -NR A S(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3 or -B(OR A )2, or two R attached to the same carbon atom 2 Examples of =O or =S are taken together; R Aeach occurrence is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or R A two occurrences of are joined together with the intervening atoms to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; and Ring A is an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

[0414] In certain embodiments, each instance of R is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)ORA 、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A)2, -NR A C(=NR A )R A , -NR A C(=NR A ) OR A , -NR A C(=NR A )SR A , -NR A C(=NR A )N(R A )2, -NR A S(=O)R A , -NR A S(=O)OR A , -NR A S(=O)SR A , -NR A S(=O)N(R A )2, -NR A S(=O)2R A , -NR A S(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2. In certain embodiments, R 2 At least one example of is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A、-N3、-NO、-N(R A )2、-NO2、-C(=O)R A 、-C(=O)OR A 、-C(=O)SR A 、-C(=O)N(R A )2、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )SR A 、-C(=NR A )N(R A )2、-S(=O)R A 、-S(=O)OR A 、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A)2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR A S(=O)2OR A 、-NR A S(=O)2SR A 、-NR A S(=O)2N(R A )2、-Si(R A )3、-Si(R A )2OR A 、-Si(R A )(OR A )2、-Si(OR A )3、-OSi(R A )3、-OSi(R A )2OR A 、-OSi(RA )(OR A )2, -OSi(OR A )3, or -B(OR A )2.

[0415] In certain embodiments, R 2 At least one instance of R is hydrogen. 2 At least two instances of R are hydrogen. 2 At least three instances of R are hydrogen. 2 At least four instances of R are hydrogen. 2 At least five instances of R are hydrogen. 2 At least six instances of R are hydrogen. 2 At least seven instances of R are hydrogen. 2 At least 8 instances of R are hydrogen. 2 All examples of are hydrogen.

[0416] In certain embodiments, ring A is an optionally substituted carbocyclyl. In certain embodiments, ring A is an optionally substituted heterocyclyl. In certain embodiments, ring A is an optionally substituted aryl. In certain embodiments, ring A is an optionally substituted heteroaryl.

[0417] In certain embodiments, the click chemistry handle has formula (VI-a):

[0418] [ka]

[0419] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0420] [ka]

[0421] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0422] [ka]

[0423] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0424] [ka]

[0425] or a salt thereof. In certain embodiments, the click chemistry handle has formula (VI-b):

[0426] [ka]

[0427] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0428] [ka]

[0429] or a salt thereof. In certain embodiments, the click chemistry handle has formula (VI-c):

[0430] [ka]

[0431] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0432] [ka]

[0433] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0434] [ka]

[0435] or a salt thereof. In certain embodiments, L comprises a click chemistry handle of formula (VI) and an optionally substituted alkylene. In certain embodiments, L comprises a click chemistry handle of formula (VI) and an optionally substituted C 1-12 In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and an optionally substituted C 1-10 In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and an optionally substituted C 1-6 In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and an unsubstituted C 1-6 In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and a substituted C 1-6 In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and a substituted C substituted with one or more oxo groups. 1-6 In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and a C substituted with one oxo group. 1-6In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and a C substituted with two oxo groups. 1-6 and alkylene. In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted n-propylene, substituted or unsubstituted isopropylene, substituted or unsubstituted n-butylene, substituted or unsubstituted tert-butylene, substituted or unsubstituted sec-butylene, substituted or unsubstituted isobutylene, substituted or unsubstituted n-pentylene, substituted or unsubstituted 3-pentanylene, substituted or unsubstituted amylene, substituted or unsubstituted neopentylene, substituted or unsubstituted 3-methylene-2-butanylene, substituted or unsubstituted tert-amylene, or substituted or unsubstituted n-hexylene. In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and unsubstituted methylene. In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and substituted methylene. In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and unsubstituted n-butylene. In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and substituted n-butylene. In certain embodiments, L comprises a click chemistry handle of formula (VI) and substituted n-butylene substituted with one or more oxo groups. In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and substituted n-butylene substituted with one oxo group. In certain embodiments, L comprises a click chemistry handle represented by formula (VI) and substituted n-butylene substituted with two oxo groups. In certain embodiments, L is

[0436] [ka]

[0437] or a salt thereof. In certain embodiments, L is

[0438] [ka]

[0439] or a salt thereof. In certain embodiments, L is

[0440] [ka]

[0441] or a salt thereof, and

[0442] [ka]

[0443] or a salt thereof. In certain embodiments, L is

[0444] [ka]

[0445] or a salt thereof, and

[0446] [ka]

[0447] or a salt thereof. In certain embodiments, L is

[0448] [ka]

[0449] or a salt thereof, and

[0450] [ka]

[0451] or a salt thereof. In certain embodiments, L is

[0452] [ka]

[0453] or a salt thereof,

[0454] [ka]

[0455] or a salt thereof, and

[0456] [ka]

[0457] or a salt thereof. In certain embodiments, L is

[0458] [ka]

[0459] or a salt thereof, and

[0460] [ka]

[0461] or a salt thereof. In certain embodiments, L is

[0462] [ka]

[0463] or a salt thereof, and

[0464] [ka]

[0465] or a salt thereof. In certain embodiments, L is

[0466] [ka]

[0467] or a salt thereof,

[0468] [ka]

[0469] or a salt thereof, and

[0470] [ka]

[0471] or a salt thereof. In certain embodiments, the click chemistry handle has formula (VII-a), (VII-b), (VII-c), or (VII-d):

[0472] [ka]

[0473] or a salt thereof, wherein: R 3Each instance of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A , -S(=O)SR A , -S(=O)N(R A )2, -S(=O)2R A , -S(=O)2OR A , -S(=O)2SR A , -S(=O)2N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)SR A , -OC(=O)N(R A )2, -OC(=NR A )R A , -OC(=NR A ) OR A , -OC(=NR A )SR A , -OC(=NR A )N(R A )2, -OS(=O)R A , -OS(=O)OR A , -OS(=O)SR A、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR A S(=O)2OR A 、-NR A S(=O)2SRA , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2 or R attached to the same carbon atom 3 two instances of together form =O or =S; and R A each occurrence is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or R A two occurrences of are joined together through the intervening atoms to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring.

[0474] In certain embodiments, R 3 each instance of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SRA 、-SSR A 、-N3、-NO、-N(R A )2、-NO2、-C(=O)R A 、-C(=O)OR A 、-C(=O)SR A 、-C(=O)N(R A )2、-C(=NR A )R A 、-C(=NR A )OR A 、-C(=NR A )SR A 、-C(=NR A )N(R A )2、-S(=O)R A 、-S(=O)OR A 、-S(=O)SR A 、-S(=O)N(R A )2、-S(=O)2R A 、-S(=O)2OR A 、-S(=O)2SR A 、-S(=O)2N(R A )2、-OC(=O)R A 、-OC(=O)OR A 、-OC(=O)SR A 、-OC(=O)N(R A )2、-OC(=NR A )R A 、-OC(=NR A )OR A 、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SRA 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A 、-NR A S(=O)N(R A )2、-NR A S(=O)2R A 、-NR A S(=O)2OR A 、-NR A S(=O)2SR A 、-NR A S(=O)2N(R A )2、-Si(R A )3、-Si(R A )2OR A 、-Si(R A )(OR A )2、-Si(OR A )3、-OSi(R A )3、-OSi(RA )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2. In certain embodiments, R 3 At least one example of is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR A , -SCN, -SR A , -SSR A , -N3, -NO, -N(R A )2, -NO2, -C(=O)R A , -C(=O)OR A , -C(=O)SR A , -C(=O)N(R A )2, -C(=NR A )R A , -C(=NR A ) OR A , -C(=NR A )SR A , -C(=NR A )N(R A )2, -S(=O)R A , -S(=O)OR A , -S(=O)SR A , -S(=O)N(R A )2, -S(=O)2R A , -S(=O)2OR A , -S(=O)2SR A , -S(=O)2N(R A )2, -OC(=O)R A , -OC(=O)OR A , -OC(=O)SR A , -OC(=O)N(R A )2, -OC(=NR A )R A , -OC(=NR A ) OR A、-OC(=NR A )SR A 、-OC(=NR A )N(R A )2、-OS(=O)R A 、-OS(=O)OR A 、-OS(=O)SR A 、-OS(=O)N(R A )2、-OS(=O)2R A 、-OS(=O)2OR A 、-OS(=O)2SR A 、-OS(=O)2N(R A )2、-ON(R A )2、-SC(=O)R A 、-SC(=O)OR A 、-SC(=O)SR A 、-SC(=O)N(R A )2、-SC(=NR A )R A 、-SC(=NR A )OR A 、-SC(=NR A )SR A 、-SC(=NR A )N(R A )2、-NR A C(=O)R A 、-NR A C(=O)OR A 、-NR A C(=O)SR A 、-NR A C(=O)N(R A )2、-NR A C(=NR A )R A 、-NR A C(=NR A )OR A 、-NR A C(=NR A )SR A 、-NR A C(=NR A )N(R A )2、-NR A S(=O)R A 、-NR A S(=O)OR A 、-NR A S(=O)SR A, -NR A S(=O)N(R A )2, -NR A S(=O)2R A , -NR A S(=O)2OR A , -NR A S(=O)2SR A , -NR A S(=O)2N(R A )2, -Si(R A )3, -Si(R A )2OR A , -Si(R A )(OR A )2, -Si(OR A )3, -OSi(R A )3, -OSi(R A )2OR A , -OSi(R A )(OR A )2, -OSi(OR A )3, or -B(OR A )2.

[0475] In certain embodiments, R 3 At least one instance of R is hydrogen. 3 At least two instances of R are hydrogen. 3 At least three instances of R are hydrogen. 3 At least four instances of R are hydrogen. 3 At least five instances of R are hydrogen. 3 At least six instances of R are hydrogen. 3 At least seven instances of R are hydrogen. 3 At least 8 instances of R are hydrogen. 3 At least 9 instances of R are hydrogen. 3 All examples of R are hydrogen. 3 At least one example of R is halogen.3 At least two instances of R are halogen. 3 At least three instances of R are halogen. 3 At least four instances of R are halogen. 3 At least five instances of R are halogen. 3 At least six instances of R are halogen. 3 At least seven instances of R are halogen. 3 At least 8 instances of R are halogen. 3 All examples of R are halogen. 3 At least one example of R is fluorine. 3 At least two instances of R are fluorine. 3 At least three instances of R are fluorine. 3 At least four instances of R are fluorine. 3 At least five instances of R are fluorine. 3 At least six instances of R are fluorine. 3 At least seven instances of R are fluorine. 3 At least 8 instances of R are fluorine. 3 All examples of R are fluorine. 3 Two examples of halogens are R 3 Nine examples of R are hydrogen. 3 Two examples of fluorine and R 3 Nine examples of are hydrogen.

[0476] In certain embodiments, the click chemistry handle has the formula

[0477] [ka]

[0478] It has. In certain embodiments, the click chemistry handle has the formula

[0479] [ka]

[0480] It has. In certain embodiments, the click chemistry handle has the formula

[0481] [ka]

[0482] It has. In certain embodiments, the click chemistry handle has the formula

[0483] [ka]

[0484] It has. In certain embodiments, the click chemistry handle has the formula

[0485] [ka]

[0486] It has. In certain embodiments, the click chemistry handle has the formula

[0487] [ka]

[0488] It has. In certain embodiments, the click chemistry handle has the formula

[0489] [ka]

[0490] It has. In certain embodiments, the click chemistry handle has the formula

[0491] [ka]

[0492] (has. In certain embodiments, the click chemistry handle has the formula

[0493] [ka]

[0494] It has. In certain embodiments, the click chemistry handle has the formula

[0495] [ka]

[0496] It has. In certain embodiments, the click chemistry handle has the formula

[0497] [ka]

[0498] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0499] [ka]

[0500] or a salt thereof. In certain embodiments, the click chemistry handle has the formula

[0501] [ka]

[0502] It has. In certain embodiments, the click chemistry handle has the formula

[0503] [ka]

[0504] It has. In certain embodiments, the click chemistry handle has the formula

[0505] [ka]

[0506] It has. In certain embodiments, the click chemistry handle has the formula

[0507] [ka]

[0508] It has. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c), or (VII-d) and an optionally substituted alkylene. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c), or (VII-d) and an optionally substituted C1-12 In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c) or (VII-d) and optionally substituted C 1-10 In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c) or (VII-d) and optionally substituted C 1-6 In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c) or (VII-d) and an unsubstituted C 1-6 In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c) or (VII-d) and a substituted C 1-6 In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c) or (VII-d), and a substituted C substituted with one or more oxo groups. 1-6 In certain embodiments, L comprises a click chemistry handle represented by formula (VII-a), (VII-b), (VII-c), or (VII-d), and a substituted C substituted with one oxo group. 1-6 In certain embodiments, L comprises a click chemistry handle represented by formula (VII-a), (VII-b), (VII-c), or (VII-d), and a substituted C substituted with two oxo groups. 1-6In certain embodiments, L comprises a click chemistry handle represented by formula (VII-a), (VII-b), (VII-c), or (VII-d), and substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted n-propylene, substituted or unsubstituted isopropylene, substituted or unsubstituted n-butene, substituted or unsubstituted tert-butylene, substituted or unsubstituted sec-butylene, substituted or unsubstituted isobutylene, substituted or unsubstituted n-pentylene, substituted or unsubstituted 3-pentanylene, substituted or unsubstituted amylene, substituted or unsubstituted neopentylene, substituted or unsubstituted 3-methylene-2 ​​butanylene, substituted or unsubstituted tert-amylene, or substituted or unsubstituted n-hexylene. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c), or (VII-d) and an unsubstituted methylene. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c), or (VII-d) and a substituted methylene. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c), or (VII-d) and an unsubstituted n-butylene. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c), or (VII-d) and a substituted n-butylene. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c) or (VII-d) and a substituted n-butylene substituted with one or more oxo groups. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c) or (VII-d) and a substituted n-butylene substituted with one oxo group. In certain embodiments, L comprises a click chemistry handle of formula (VII-a), (VII-b), (VII-c) or (VII-d) and a substituted n-butylene substituted with two oxo groups. In certain embodiments, L is

[0509] [ka]

[0510] or a salt thereof. In certain embodiments, L is

[0511] [ka]

[0512] or a salt thereof. In certain embodiments, L is

[0513] [ka]

[0514] or a salt thereof, and

[0515] [ka]

[0516] or a salt thereof. In certain embodiments, L is

[0517] [ka]

[0518] or a salt thereof, and

[0519] [ka]

[0520] or a salt thereof. In certain embodiments, L is

[0521] [ka]

[0522] or a salt thereof, and

[0523] [ka]

[0524] or a salt thereof. In certain embodiments, L is

[0525] [ka]

[0526] or a salt thereof,

[0527] [ka]

[0528] or a salt thereof, and

[0529] [ka]

[0530] or a salt thereof. In certain embodiments, L is

[0531] [ka]

[0532] or a salt thereof, and

[0533] [ka]

[0534] or a salt thereof. In certain embodiments, L is

[0535] [ka]

[0536] or a salt thereof, and

[0537] [ka]

[0538] or a salt thereof. In certain embodiments, L is

[0539] [ka]

[0540] or a salt thereof,

[0541] [ka]

[0542] or a salt thereof, and

[0543] [ka]

[0544] or a salt thereof. In certain embodiments, L is

[0545] [ka]

[0546] or a salt thereof. In certain embodiments, L is

[0547] [ka]

[0548] or a salt thereof. In certain embodiments, L is

[0549] [ka]

[0550] or a salt thereof. In certain embodiments, L is

[0551] [ka]

[0552] or a salt thereof. In certain embodiments, L is

[0553] [ka]

[0554] or a salt thereof. In certain embodiments, L is

[0555] [ka]

[0556] or a salt thereof. In certain embodiments, L is

[0557] [ka]

[0558] or a salt thereof. In certain embodiments, L is

[0559] [ka]

[0560] or a salt thereof. In certain embodiments, L is

[0561] [ka]

[0562] or a salt thereof. In certain embodiments, L is

[0563] [ka]

[0564] or a salt thereof. In certain embodiments, L is

[0565] [ka]

[0566] or a salt thereof. In certain embodiments, the compound has formula (Iai), (Ia-ii), (Ibi), or (Ib-ii):

[0567] [ka]

[0568] or a salt thereof. In certain embodiments, the compound has the formula (Iai):

[0569] [ka]

[0570] or a salt thereof. In certain embodiments, the compound has formula (Ia-ii):

[0571] [ka]

[0572] or a salt thereof. In certain embodiments, the compound has the formula (Ibi):

[0573] [ka]

[0574] or a salt thereof. In certain embodiments, the compound has formula (Ib-ii):

[0575] [ka]

[0576] or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 (5'-CCACGCGTGGAACCCTTGGGATCCA-3' (SEQ ID NO:42). In certain embodiments, at least one strand of the oligonucleotide has a sequence that is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to 5'-CCACGCGTGGAACCCTTGGGATCCA-3' (SEQ ID NO:42). In certain embodiments, at least one strand of the oligonucleotide has a sequence that is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% identical to 5'-TGGAGTCAAGGTCCTCTGATGCCAT-3' (SEQ ID NO:70).

[0577] In certain embodiments, the oligonucleotide comprises at least about 10 bases. In certain embodiments, the oligonucleotide comprises at least about 15 bases. In certain embodiments, the oligonucleotide comprises at least about 20 bases. In certain embodiments, the oligonucleotide comprises at least about 25 bases. In certain embodiments, the oligonucleotide comprises at least about 30 bases. In certain embodiments, the oligonucleotide comprises at least about 35 bases. In certain embodiments, the oligonucleotide comprises at least about 40 bases. In certain embodiments, the oligonucleotide comprises at least about 45 bases. In certain embodiments, the oligonucleotide comprises at least about 50 bases. In certain embodiments, the oligonucleotide comprises about 10 to about 50 bases. In certain embodiments, the oligonucleotide comprises about 15 to about 50 bases. In certain embodiments, the oligonucleotide comprises about 20 to about 50 bases. In certain embodiments, the oligonucleotide comprises about 25 to about 50 bases. In certain embodiments, the oligonucleotide comprises about 25 to about 45 bases. In certain embodiments, the oligonucleotide comprises about 25 to about 40 bases. In certain embodiments, the oligonucleotide comprises about 25 to about 35 bases. In certain embodiments, the oligonucleotide comprises about 25 to about 30 bases. In certain embodiments, the oligonucleotide comprises 10 bases. In certain embodiments, the oligonucleotide comprises 15 bases. In certain embodiments, the oligonucleotide comprises 20 bases. In certain embodiments, the oligonucleotide comprises 25 bases (e.g., the oligonucleotide is a 25-mer). In certain embodiments, the oligonucleotide comprises 30 bases. In certain embodiments, the oligonucleotide comprises 35 bases. In certain embodiments, the oligonucleotide comprises 40 bases. In certain embodiments, the oligonucleotide comprises 45 bases. In certain embodiments, the oligonucleotide comprises 50 bases.

[0578] In certain embodiments, the oligonucleotide comprises about 10 to about 50 bases, and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO: 61), isoEGWRW (SEQ ID NO: 62), DDGGGDDDFF (SEQ ID NO: 32), GGSSSGSGNDEEFQ (SEQ ID NO: 59), GGGGGDPDPD (SEQ ID NO: 54), GGGGGDPDPDFF (SEQ ID NO: 55), GGGGGGDPDPD (SEQ ID NO: 57), GDGDGDGDGDFF (SEQ ID NO: 53), GDDGDGDGDFF (SEQ ID NO: 51), NNGGGNNNFF (SEQ ID NO: 65), or DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, wherein Cy is cysteic acid. In certain embodiments, the oligonucleotide comprises about 25 to about 50 bases, and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO: 61), isoEGWRW (SEQ ID NO: 62), DDGGGDDDFF (SEQ ID NO: 32), GGSSSGSGNDEEFQ (SEQ ID NO: 59), GGGGGDPDPD (SEQ ID NO: 54), GGGGGDPDPDFF (SEQ ID NO: 55), GGGGGGDPDPD (SEQ ID NO: 57), GDGDGDGDGDFF (SEQ ID NO: 53), GDDGDGDGDFF (SEQ ID NO: 51), NNGGGNNNFF (SEQ ID NO: 65), or DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, wherein Cy is cysteic acid. In certain embodiments, the oligonucleotide comprises about 25 to about 45 bases, and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO: 61), isoEGWRW (SEQ ID NO: 62), DDGGGDDDFF (SEQ ID NO: 32), GGSSSGSGNDEEFQ (SEQ ID NO: 59), GGGGGDPDPD (SEQ ID NO: 54), GGGGGDPDPDFF (SEQ ID NO: 55), GGGGGGDPDPD (SEQ ID NO: 57), GDGDGDGDGDFF (SEQ ID NO: 53), GDDGDGDGDFF (SEQ ID NO: 51), NNGGGNNNFF (SEQ ID NO: 65), or DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, wherein Cy is cysteic acid.In certain embodiments, the oligonucleotide comprises about 25 to about 40 bases, and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO: 61), isoEGWRW (SEQ ID NO: 62), DDGGGDDDFF (SEQ ID NO: 32), GGSSSGSGNDEEFQ (SEQ ID NO: 59), GGGGGDPDPD (SEQ ID NO: 54), GGGGGDPDPDFF (SEQ ID NO: 55), GGGGGGDPDPD (SEQ ID NO: 57), GDGDGDGDGDFF (SEQ ID NO: 53), GDDGDGDGDFF (SEQ ID NO: 51), NNGGGNNNFF (SEQ ID NO: 65), or DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, wherein Cy is cysteic acid. In certain embodiments, the oligonucleotide comprises about 25 to about 35 bases, and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO: 61), isoEGWRW (SEQ ID NO: 62), DDGGGDDDFF (SEQ ID NO: 32), GGSSSGSGNDEEFQ (SEQ ID NO: 59), GGGGGDPDPD (SEQ ID NO: 54), GGGGGDPDPDFF (SEQ ID NO: 55), GGGGGGDPDPD (SEQ ID NO: 57), GDGDGDGDGDFF (SEQ ID NO: 53), GDDGDGDGDFF (SEQ ID NO: 51), NNGGGNNNFF (SEQ ID NO: 65), or DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, wherein Cy is cysteic acid. In certain embodiments, the oligonucleotide comprises about 25 to about 30 bases, and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO: 61), isoEGWRW (SEQ ID NO: 62), DDGGGDDDFF (SEQ ID NO: 32), GGSSSGSGNDEEFQ (SEQ ID NO: 59), GGGGGDPDPD (SEQ ID NO: 54), GGGGGDPDPDFF (SEQ ID NO: 55), GGGGGGDPDPD (SEQ ID NO: 57), GDGDGDGDGDFF (SEQ ID NO: 53), GDDGDGDGDFF (SEQ ID NO: 51), NNGGGNNNFF (SEQ ID NO: 65), or DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, wherein Cy is cysteic acid.In certain embodiments, the oligonucleotide comprises 25 bases (by way of example, the oligonucleotide is a 25-mer), and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO: 61), isoEGWRW (SEQ ID NO: 62), DDGGGDDDFF (SEQ ID NO: 32), GGSSSGSGNDEEFQ (SEQ ID NO: 59), GGGGGDPDPD (SEQ ID NO: 54), GGGGGDPDPDFF (SEQ ID NO: 55), GGGGGGDPDPD (SEQ ID NO: 57), GDGDGDGDGDFF (SEQ ID NO: 53), GDDGDGDGDFF (SEQ ID NO: 51), NNGGGNNNFF (SEQ ID NO: 65), or DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, wherein Cy is cysteic acid.

[0579] In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO:61), isoEGWRW (SEQ ID NO:62), DDGGGDDDFF (SEQ ID NO:32), GGSSSGSGNDEEFQ (SEQ ID NO:59), GGGGGDPDPD (SEQ ID NO:54), GGGGGDPDPDFF (SEQ ID NO:55), GGGGGGDPDPD (SEQ ID NO:57), GDGDGDGDGDFF (SEQ ID NO:53), GDDGDGDGDFF (SEQ ID NO:51), NNGGGNNNFF (SEQ ID NO:65), or DDGGGCyCyCyFF (SEQ ID NO:45), or a salt thereof, wherein Cy is cysteic acid. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GPPPPPPPPG (SEQ ID NO:61), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence isoEGWRW (SEQ ID NO: 62), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence DDGGGDDDFF (SEQ ID NO: 32), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GGSSSGSGNDEEFQ (SEQ ID NO: 59), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GGGGGDPDPD (SEQ ID NO: 54), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GGGGGDPDPDFF (SEQ ID NO: 55), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GGGGGGDPDPD (SEQ ID NO: 57), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GDGDGDGDGDFF (SEQ ID NO: 53), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GDDGDGDGDFF (SEQ ID NO: 51), or a salt thereof.In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence NNGGGNNNFF (SEQ ID NO: 65), or a salt thereof. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, where Cy is cysteic acid. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises a sequence selected from GPPPPPPPPG (SEQ ID NO:61), isoEGWRW (SEQ ID NO:62), DDGGGDDDFF (SEQ ID NO:32), GGSSSGSGNDEEFQ (SEQ ID NO:59), GGGGGDPDPD (SEQ ID NO:54), GGGGGDPDPDFF (SEQ ID NO:55), GGGGGGDPDPD (SEQ ID NO:57), GDGDGDGDGDFF (SEQ ID NO:53), GDDGDGDGDFF (SEQ ID NO:51), NNGGGNNNFF (SEQ ID NO:65), or DDGGGCyCyCyFF (SEQ ID NO:45), where Cy is cysteic acid. In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GPPPPPPPPG (SEQ ID NO:61). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence isoEGWRW (SEQ ID NO: 62). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence DDGGGDDDFF (SEQ ID NO: 32). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GGSSSGSGNDEEFQ (SEQ ID NO: 59). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GGGGGDPDPD (SEQ ID NO: 54). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GGGGGDPDPDFF (SEQ ID NO: 55). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GGGGGGDPDPD (SEQ ID NO: 57). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GDGDGDGDGDFF (SEQ ID NO: 53).In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence GDDGDGDGDFF (SEQ ID NO: 51). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence NNGGGNNNFF (SEQ ID NO: 65). In certain embodiments, the oligonucleotide comprises Q24 and the polypeptidyl group comprises the sequence DDGGGCyCyCyFF (SEQ ID NO: 45), where Cy is cysteic acid.

[0580] In certain embodiments, Y further comprises at least one biotin moiety. In certain embodiments, Y further comprises a biotin moiety. In certain embodiments, Y further comprises two or more biotin moieties. In certain embodiments, at least one biotin moiety is a bis-biotin moiety. In certain embodiments, the biotin moiety is a bis-biotin moiety. In some embodiments, Y further comprises a tag sequence. In some embodiments, the tag sequence comprises at least one biotin ligase recognition sequence that allows biotinylation of Y (e.g., incorporation of one or more biotin molecules comprising biotin and bis-biotin moieties). In some embodiments, the tag sequence comprises two biotin ligase recognition sequences oriented in tandem. In some embodiments, a biotin ligase recognition sequence refers to an amino acid sequence recognized by a biotin ligase that catalyzes the covalent bond between the sequence and a biotin molecule. Each biotin ligase recognition sequence of a tag sequence can be covalently linked to a biotin moiety, such that a tag sequence having multiple biotin ligase recognition sequences can be covalently linked to multiple biotin molecules. A region of a tag sequence having one or more biotin ligase recognition sequences can generally be referred to as a biotinylation tag or biotinylation sequence. In some embodiments, bis-biotin or a bis-biotin moiety can refer to two biotins bound to two biotin ligase recognition sequences oriented in tandem. In some embodiments, Y comprises at least one biotin ligase recognition sequence having a biotin moiety attached thereto. In some embodiments, Y comprises at least one biotin ligase recognition sequence having a bis-biotin moiety attached thereto. In some embodiments, Y comprises at least two biotin ligase recognition sequences having biotin moieties attached thereto. In some embodiments, Y comprises at least two biotin ligase recognition sequences having bis-biotin moieties attached thereto. In certain embodiments, the oligonucleotide comprises Q24 and Y further comprises at least one biotin moiety. In certain embodiments, the oligonucleotide comprises Q24 and Y further comprises a biotin moiety.In certain embodiments, the oligonucleotide comprises Q24 and Y further comprises two or more biotin moieties. In certain embodiments, the oligonucleotide comprises Q24 and at least one biotin moiety is a bis-biotin moiety. In certain embodiments, the oligonucleotide comprises Q24 and the biotin moiety is a bis-biotin moiety. In some embodiments, the oligonucleotide comprises Q24 and Y further comprises a tag sequence. In some embodiments, the oligonucleotide comprises Q24 and Y comprises at least one biotin ligase recognition sequence having a biotin moiety attached thereto. In some embodiments, the oligonucleotide comprises Q24 and Y comprises at least one biotin ligase recognition sequence having a bis-biotin moiety attached thereto. In some embodiments, the oligonucleotide comprises Q24 and Y comprises at least two biotin ligase recognition sequences having biotin moieties attached thereto. In some embodiments, the oligonucleotide comprises Q24 and Y comprises at least two biotin ligase recognition sequences having biotin moieties attached thereto.

[0581] In certain embodiments, Y further comprises an avidin protein. In certain embodiments, the avidin protein is avidin, streptavidin, traptavidin, tamavidin, bradavidin, xenavidin, or a homolog or variant thereof. In certain embodiments, the avidin protein is avidin, streptavidin, traptavidin, tamavidin, bradavidin, or xenavidin. In certain embodiments, the avidin protein is avidin. In certain embodiments, the avidin protein is streptavidin. In certain embodiments, the avidin protein is traptavidin. In certain embodiments, the avidin protein is tamavidin. In certain embodiments, the avidin protein is bradavidin. In certain embodiments, the avidin protein is xenavidin. In certain embodiments, the avidin protein is in a monomeric, dimeric, or tetrameric form. In certain embodiments, the avidin protein is in a monomeric form. In certain embodiments, the avidin protein is in a dimeric form. In certain embodiments, the avidin protein is in a tetrameric form. In some embodiments, the avidin protein is streptavidin in a tetrameric form (e.g., a homotetramer). In certain embodiments, the oligonucleotide comprises Q24, and Y further comprises an avidin protein. In certain embodiments, the oligonucleotide comprises Q24, and the avidin protein is avidin, streptavidin, traptavidin, tamavidin, bradyvidin, xenavidin, or a homolog or variant thereof. In certain embodiments, the oligonucleotide comprises Q24, and the avidin protein is streptavidin. In certain embodiments, the oligonucleotide comprises Q24, and the avidin protein is a monomeric, dimeric, or tetrameric form. In certain embodiments, the oligonucleotide comprises Q24 and the avidin protein is in a monomeric form. In certain embodiments, the oligonucleotide comprises Q24 and the avidin protein is in a dimeric form.In certain embodiments, the oligonucleotide comprises Q24 and the avidin protein is in tetrameric form, hi some embodiments, the oligonucleotide comprises Q24 and the avidin protein is streptavidin in tetrameric form (e.g., homotetramer).

[0582] In some embodiments, the avidin protein comprises one or more biotin binding sites. In some embodiments, the one or more biotin binding sites of the avidin protein provide attachment sites for Y. In some embodiments, the one or more biotin binding sites of the avidin protein provide attachment sites for Y, where Y further comprises at least one biotin moiety. In some embodiments, the at least one biotin moiety binds to one or more biotin binding sites of the avidin protein. In some embodiments, the at least one biotin moiety is a bis-biotin moiety, where the bis-biotin moiety is bound to two biotin binding sites on the avidin protein.

[0583] In certain embodiments, Y is immobilized on a surface. In certain embodiments, the oligonucleotide comprises Q24 and Y is immobilized on a surface. As used herein, in some embodiments, surface refers to the surface of a substrate or solid support. In some embodiments, solid support refers to a material, layer, or other structure having a surface, such as a receiving surface, that can support deposited materials, such as the compounds described herein. In some embodiments, the receiving surface of a substrate may optionally have one or more features, including nanoscale or microscale recessed features, such as an array of sample wells. In some embodiments, an array is a planar arrangement of elements, such as sensors or sample wells. An array may be one-dimensional or two-dimensional. A one-dimensional array is an array having one column or row of elements in the first dimension and multiple columns or rows in the second dimension. The number of columns or rows in the first and second dimensions may be the same or different. In some embodiments, an array may have a number of elements, e.g., 102 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 The sample well may comprise a surface. In some embodiments, the surface is functionalized with a complementary functional moiety configured for binding (e.g., covalently or non-covalently) to Y. In some embodiments, the complementary functional moiety is a biotin moiety. In some embodiments, the complementary functional moiety is a bis-biotin moiety. In some embodiments, Y is immobilized on the bottom or sidewall surface of the sample well. In some embodiments, surface immobilization of Y allows the compound to be confined to a desired region of the surface for real-time monitoring of a reaction involving the compound. In certain embodiments, the compound is immobilized on the surface via Y. In certain embodiments, the compound is immobilized on the surface via Y so that the compound can be monitored without interference from other reaction components in solution. In some embodiments, surface immobilization of Y allows the compound to be confined to a desired region of the surface for real-time monitoring of a reaction involving the compound.

[0584] Preparation method In another embodiment, a compound of formula (II): ZLY(II) or a salt thereof, comprising reacting a compound of formula (I): LY(I) or a salt thereof with a compound of formula Z-N3 or a salt thereof During the ceremony: L comprises a polypeptide group; Y is an oligonucleotide; and Z is a polypeptide. Methods are provided herein.

[0585] In certain embodiments, reacting a compound of Formula (I) or a salt thereof with a compound of Formula Z-N3 or a salt thereof comprises a click chemistry reaction. In certain embodiments, reacting a compound of Formula (I) or a salt thereof with a compound of Formula Z-N3 or a salt thereof comprises an azide-alkyne cycloaddition.

[0586] In certain embodiments, the method comprises reacting a compound of formula L-N3, or a salt thereof, with a compound of formula Y-propargyl, or a salt thereof, to produce a compound of formula (I): LY(I) or a salt thereof.

[0587] In certain embodiments, a polypeptidyl group comprises at least 10 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 11 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 12 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 13 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 14 amino acid residues. In certain embodiments, a polypeptidyl group comprises at least 15 amino acid residues. In certain embodiments, a polypeptidyl group comprises 10 to 15 amino acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 10 to 14 amino acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 10 to 13 amino acid residues (inclusive). In certain embodiments, a polypeptidyl group comprises 10 to 12 amino acid residues (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues. In certain embodiments, the polypeptidyl group comprises 11 amino acid residues. In certain embodiments, the polypeptidyl group comprises 12 amino acid residues.

[0588] In certain embodiments, the polypeptidyl group is at least about 30 Å in length. In certain embodiments, the polypeptidyl group is at least about 33 Å in length. In certain embodiments, the polypeptidyl group is at least about 35 Å in length. In certain embodiments, the polypeptidyl group is about 25 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 45 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 40 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 25 Å to about 35 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 30 Å to about 35 Å in length, inclusive. In certain embodiments, the polypeptidyl group is about 33 Å in length.

[0589] In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive), and is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive), and is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive), and is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues and is about 25 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 11 amino acid residues and is about 25 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 12 amino acid residues and is about 25 Å to about 50 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues, inclusive, and is about 25 Å to about 45 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues, inclusive, and is about 25 Å to about 45 Å in length, inclusive. In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive), and is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues, and is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 11 amino acid residues, and is about 25 Å to about 45 Å in length (inclusive).In certain embodiments, the polypeptidyl group comprises 12 amino acid residues and is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive) and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive) and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive) and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues, and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 11 amino acid residues, and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 12 amino acid residues, and is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive), and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive) and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive) and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive) and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues and is about 25 Å to about 35 Å in length (inclusive).In certain embodiments, the polypeptidyl group comprises 11 amino acid residues and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 12 amino acid residues and is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive) and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive) and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive) and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 amino acid residues, and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 11 amino acid residues, and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 12 amino acid residues, and is about 30 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 10 to 15 amino acid residues (inclusive), and is about 33 Å in length. In certain embodiments, the polypeptidyl group comprises 10 to 14 amino acid residues (inclusive), and is approximately 33 Å in length. In certain embodiments, the polypeptidyl group comprises 10 to 13 amino acid residues (inclusive), and is approximately 33 Å in length. In certain embodiments, the polypeptidyl group comprises 10 to 12 amino acid residues (inclusive), and is approximately 33 Å in length. In certain embodiments, the polypeptidyl group comprises 10 amino acid residues, and is approximately 33 Å in length.In certain embodiments, the polypeptidyl group comprises 11 amino acid residues and is approximately 33 Å in length. In certain embodiments, the polypeptidyl group comprises 12 amino acid residues and is approximately 33 Å in length.

[0590] In certain embodiments, the polypeptidyl group comprises at least five negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises at least six negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises three to six (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises four to six (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises five to six (inclusive) negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises four negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises five negatively charged moieties at physiological pH. In certain embodiments, the polypeptidyl group comprises six negatively charged moieties at physiological pH.

[0591] In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 50 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 45 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 40 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 25 Å to about 35 Å in length (inclusive). In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) negatively charged moieties at physiological pH, and the polypeptidyl group is about 30 Å to about 35 Å in length. In certain embodiments, the polypeptidyl group comprises 3 to 6 (inclusive) n...

Claims

1. Compounds of formula (I): L-Y (I) or its salts (In the formula: L comprises a polypeptide group; and Y comprises an oligonucleotide).

2. Compound of formula (II): Z-L-Y(II) or its salts (In the formula: L comprises a polypeptide group; Y comprises an oligonucleotide; and Z is a polypeptide).

3. The compound according to any one of claims 1 and 2, wherein the polypeptidyl group comprises 5 to 20 amino acid residues.

4. The compound of any one of claims 1 and 2, wherein the polypeptidyl group is from about 20 Å to about 75 Å in length.

5. The compound according to any one of claims 1 and 2, wherein the polypeptidyl group comprises 1 to 10 negatively charged moieties at physiological pH.

6. The compound according to any one of claims 1 and 2, wherein the polypeptidyl group comprises 1 to 15 aspartic acid residues.

7. The compound according to any one of claims 1 and 2, wherein the polypeptidyl group comprises 1 to 10 phenylalanine residues.

8. The compound according to any one of claims 1 and 2, wherein the polypeptidyl group comprises 1 to 10 glycine residues.

9. The compound according to any one of claims 1 and 2, wherein the polypeptidyl group comprises 1 to 5 proline residues.

10. The compound according to any one of claims 1 and 2, wherein the polypeptidyl group comprises 1 to 5 GP repeats.

11. The polypeptide group is 【Chemical 1】 or a salt thereof.

12. The polypeptide group is 【Chemistry 2】 or a salt thereof.

13. 3. The compound of claim 1, wherein the polypeptidyl group comprises a sequence selected from GPPPPPPPPPG (SEQ ID NO: 61), isoEGWRW (SEQ ID NO: 62), DDGGGDDDFF (SEQ ID NO: 32), GGSSSGSGNDEEFQ (SEQ ID NO: 59), GGGGGDPDPD (SEQ ID NO: 54), GGGGGDPDPDFFF (SEQ ID NO: 55), GGGGGGGPDPDPD (SEQ ID NO: 57), GDGDGDGDGDFF (SEQ ID NO: 53), GDDGDGDGDFF (SEQ ID NO: 51), NNGGGNNNFF (SEQ ID NO: 65), or DDGGGCyCyCyFF (SEQ ID NO: 45), or a salt thereof, wherein Cy is cysteic acid.

14. The compound of any one of claims 1 to 13, wherein the polypeptidyl group comprises the sequence DDGGGDDDFF (SEQ ID NO: 32), or a salt thereof.

15. 3. The compound of claim 1, wherein L further comprises at least one of an optionally substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted heteroalkylene, an optionally substituted heteroalkenylene, an optionally substituted heteroalkynylene, an optionally substituted heterocyclylene, an optionally substituted carbocyclylene, an optionally substituted arylene, an optionally substituted heteroarylene, a peptidyl group, a dipeptidyl group, a polypeptidyl group, a click chemistry handle, or a combination thereof.

16. 3. The compound of claim 1, wherein L further comprises a click chemistry handle.

17. 17. The compound of claim 16, wherein the click chemistry handle comprises an alkyne.

18. 17. The compound of claim 16, wherein the click chemistry handle comprises a strained alkyne.

19. 17. The compound of claim 16, wherein the click chemistry handle comprises a cyclooctyne.

20. The click chemistry handle has formula (IV): 【Chemistry 3】 or a salt thereof: R １ Each instance of is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, -OR Ａ , -SCN, -SR Ａ , -SSR Ａ , -N ３ , -NO, -N(R Ａ ) ２ , -NO ２ , -C(=O)R Ａ , -C(=O)OR Ａ , -C(=O)SR Ａ , -C(=O)N(R Ａ ) ２ , -C(=NR Ａ ) R Ａ , -C(=NR Ａ ) OR Ａ , -C(=NR Ａ )SR Ａ , -C(=NR Ａ ) N (R Ａ ) ２ , -S(=O)R Ａ , -S(=O)OR Ａ , -S(=O)SR Ａ , -S(=O)N(R Ａ ) ２ , -S(=O) ２ R Ａ , -S(=O) ２ OR Ａ , -S(=O) ２ SR Ａ , -S(=O) ２ N (R Ａ ) ２ , —OC(═O)R Ａ , -OC(=O)OR Ａ , -OC(=O)SR Ａ , -OC(=O)N(R Ａ ) ２ , -OC(=NR Ａ ) R Ａ 、-OC(=NR Ａ )OR Ａ 、-OC(=NR Ａ )SR Ａ 、-OC(=NR Ａ )N(R Ａ ) ２ 、-OS(=O)R Ａ 、-OS(=O)OR Ａ 、-OS(=O)SR Ａ 、-OS(=O)N(R Ａ ) ２ 、-OS(=O) ２ R Ａ 、-OS(=O) ２ OR Ａ 、-OS(=O) ２ SR Ａ 、-OS(=O) ２ N(R Ａ ) ２ 、-ON(R Ａ ) ２ 、-SC(=O)R Ａ 、-SC(=O)OR Ａ 、-SC(=O)SR Ａ 、-SC(=O)N(R Ａ ) ２ 、-SC(=NR Ａ )R Ａ 、-SC(=NR Ａ )OR Ａ 、-SC(=NR Ａ )SR Ａ 、-SC(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ C(=O)R Ａ 、-NR Ａ C(=O)OR Ａ 、-NR Ａ C(=O)SR Ａ 、-NR Ａ C(=O)N(R Ａ ) ２ 、-NR Ａ C(=NR Ａ )R Ａ 、-NR Ａ C(=NR Ａ )OR Ａ 、-NR Ａ C(=NR Ａ )SR Ａ 、-NR Ａ C(=NR Ａ )N(R Ａ ) ２ 、-NR Ａ S(=O)R Ａ 、-NR Ａ S(=O)OR Ａ 、-NR Ａ S(=O)SR Ａ 、-NR Ａ S(=O)N(R Ａ ) ２ 、-NR Ａ S(=O) ２ R Ａ 、-NR Ａ S(=O) ２ OR Ａ 、-NR Ａ S(=O) ２ SR Ａ 、-NR Ａ S(=O) ２ N(R Ａ ) ２ 、-Si(R Ａ ) ３ 、-Si(R Ａ ) ２ OR Ａ 、-Si(R Ａ )(OR Ａ ) ２ 、-Si(OR Ａ ) ３ 、-OSi(R Ａ ) ３ 、-OSi(R Ａ ) ２ OR Ａ 、-OSi(R Ａ )(OR Ａ ) ２ 、-OSi(OR Ａ ) ３ ,または-B(OR Ａ ) ２ であり; R Ａ each occurrence is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or R Ａ two occurrences of are joined together with the intervening atoms to form an optionally substituted heterocyclyl ring or an optionally substituted heteroaryl ring; and 17. The compound of claim 16, wherein Q is CH or N.

21. The click chemistry handle has formula (IV-a): 【Chemistry 4】 17. The compound of claim 16, wherein:

22. The click chemistry handle has formula (IV-b): 【Chemistry 5】 17. The compound of claim 16, wherein:

23. R １ 21. The compound of claim 20, wherein at least one instance of is hydrogen.

24. R １ 21. The compound of claim 20, wherein all instances of are hydrogen.

25. The click chemistry handle has formula (IV-bi): 【Chemistry 6】 17. The compound of claim 16, wherein:

26. 3. The compound of claim 1, wherein L further comprises an optionally substituted alkylene.

27. L is an optionally substituted C １－１０ The compound of any one of claims 1 and 2, further comprising an alkylene.

28. L is an optionally substituted C １－６ The compound of any one of claims 1 and 2, further comprising an alkylene.

29. L is a substitution C １－１０ The compound of any one of claims 1 and 2, further comprising an alkylene.

30. L is, 【Chemistry 7】 3. The compound of claim 1, further comprising:

31. L is, 【Chemistry 8】 or a salt thereof.

32. L is, 【Chemistry 9】 or a salt thereof.

33. L is, 【Chemistry 10】 or a salt thereof.

34. 3. The compound of claim 1, wherein L further comprises an optionally substituted heterocyclylene.

35. L is, 【Chemistry 11】 or a salt thereof.

36. L is, 【Chemistry 12】 or a salt thereof.

37. The compound is 【Chemistry 13】 or a salt thereof.

38. The compound of any one of claims 1 and 2, wherein the oligonucleotide comprises Q24.

39. 3. The compound of claim 1, wherein Y further comprises a biotin moiety.

40. 40. The compound of claim 39, wherein the biotin moiety is a bis-biotin moiety.

41. 3. The compound of claim 1, wherein Y further comprises an avidin protein.

42. 42. The compound of claim 41, wherein the avidin protein is streptavidin.

43. 3. The compound according to claim 1, wherein Y is immobilized on a surface.

44. 3. The compound of claim 2, wherein the oligonucleotide and the polypeptide are separated by about 25 Å to about 75 Å.

45. Formula (II): Z-L-Y(II) or a salt thereof, said method comprising: L-Y (I) or a salt thereof, ３ or a salt thereof, (In the formula, L comprises a polypeptide group; Y is an oligonucleotide; and Z is a polypeptide. method.

46. The compound of formula (I) or a salt thereof is reacted with a compound of formula Z-N ３ or a salt thereof comprises a click chemistry reaction.

47. The compound of formula (I) or a salt thereof is reacted with a compound of formula Z-N ３ or a salt thereof comprises an azide-alkyne cycloaddition.

48. 46. ​​The method of claim 45, wherein L further comprises a click chemistry handle.

49. The click chemistry handle has formula (IV-bi): 【Chemistry 14】 or a salt thereof.

50. L is, 【Chemistry 15】 46. ​​The method of claim 45, comprising a moiety selected from:

51. Formula L-N ３ or a salt thereof with a compound of formula Y-propargyl or a salt thereof to give a compound of formula (I): L-Y (I) 46. ​​The method of claim 45, further comprising obtaining the compound of formula (I) or a salt thereof.

52. The above formula L-N ３ The compound 【Chemistry 16】 52. The method of claim 51, comprising a moiety selected from:

53. The above formula L-N ３ The compound of formula: 【Chemistry 17】 or a salt thereof.

54. The compound of formula (I) has the formula: 【Chemistry 18】 or a salt thereof.

55. A method for sequencing a polypeptide Z, said method comprising the step of: Z-L-Y(II) (In the formula, L comprises a polypeptide group; and Y is an oligonucleotide or a salt thereof with a peptidase; reacting the compound of formula (II) or a salt thereof with a peptidase in a degradation process; acquiring data during the decomposition process; analyzing the data to determine portions of the data that correspond to amino acids sequentially exposed at the termini of the polypeptide during the degradation process; optionally outputting an amino acid sequence representing said polypeptide; A method comprising:

56. Compounds of formula (I): L-Y (I) or a salt thereof with a functionalized polypeptide or a salt thereof to form a polypeptide of formula (II): Z-L-Y(II) or a salt thereof, wherein the functionalized polypeptide or salt thereof comprises a click chemistry handle, and the compound of formula (I) or a salt thereof comprises a click chemistry handle.

57. 57. The method of any one of claims 55 and 56, wherein the peptidase is an exopeptidase.

58. 57. The method of any one of claims 55 and 56, wherein the peptidase is an aminopeptidase.

59. 57. The method of any one of claims 55 and 56, wherein the peptidase is a proline aminopeptidase, a proline iminopeptidase, a glutamic / aspartic acid-specific aminopeptidase, a methionine-specific aminopeptidase, or a zinc metalloprotease.

60. 57. The method of any one of claims 55 and 56, wherein the peptidase is a TET aminopeptidase.

61. The cutting depth of the compound of formula (II) is represented by formula (X): Z-L １ -Y(X) (In the formula, L １ teeth, 【Chemistry 19】 or 【Chemistry 20】 or a salt thereof) 57. The method of any one of claims 55 and 56, wherein the cutting depth of the compound is improved compared to that of the compound of formula (I).

62. 62. The method of claim 61, wherein the cutting depth of the compound of formula (II) is improved by about 10% to about 100% compared to the cutting depth of the compound of formula (X).

63. The percentage of leads terminating at a particular residue of the compound of formula (II) is determined by determining whether the compound has the formula (X): Z-L １ -Y(X) (In the formula, L １ teeth, 【Chemical 21】 or 【Chemical 22】 or a salt thereof) 57. The method of any one of claims 55 and 56, wherein the percentage of leads terminating at a particular residue of the compound is improved compared to the percentage of leads terminating at a particular residue of the compound.

64. 64. The method of claim 63, wherein the percentage of leads terminating at a particular residue of the compound of formula (II) is improved by about 100% to about 1000% compared to the percentage of leads terminating at a particular residue of the compound of formula (X).

65. The cleavage rate of the compound of formula (II) is expressed by formula (X): Z-L １ -Y(X) (In the formula, L １ teeth, 【Chemical 23】 or 【Chemistry 24】 or a salt thereof) 57. The method of any one of claims 55 and 56, wherein the cleavage rate of the compound is improved compared to that of

66. 66. The method of claim 65, wherein the cleavage rate of the compound of formula (II) is at least 2-fold, at least 3-fold, or at least 4-fold higher than the cleavage rate of the compound of formula (X).

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