Modification of peptoids to form thioether (POLY)macrocyclic structures

Abstract

The present disclosure is concerned with methods of chemically modifying a compound to install one or more thioether or selenoether linkages via a reaction with PapB. Also disclosed are compounds formed using methods of chemically modifying a peptoid sequence. Also disclosed are thioether or selenoether compounds produced by a disclose method. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present technology.

Description

SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1ENZYMATIC MODIFICATION OF COMPOUNDS COMPRISING ONE OR MOREN-SUBSTITUTED GLYCINES (PEPTOIDS) TO FORM THIOETHER (POLY)MACROCYCLIC STRUCTURESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No.63 / 790,904, filed on April 18, 2025, the contents of which are incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grant number GM 126956 awarded by the National Institutes of Health. The government has certain rights in the invention.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0003] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format and hereby incorporated by reference in its entirety. The.xml copy, created on April 13, 2026, is titled “Sequence.xml” and is 29,737 bytes in size.BACKGROUND

[0004] Peptide-based therapeutics have become increasingly important but often exhibit short serum half-lives due to reduction of disulfide bonds and / or proteolytic degradation. While chemical approaches (e.g., cyclization, non-proteinogenic amino acids, and other derivatizations) can improve stability, they are constrained in the architectures and sequences they can access.

[0005] Enzymatic post-translational modification systems, including RiPP maturases such as radical S-adenosylmethionine (rSAM) enzymes, can create structurally diverse and conformationally constrained peptides (e.g., via thioether crosslinks). One such rSAM enzyme, PapB, has recently been demonstrated to install intra- and interpeptide thioether crosslinks in synthetic constructs.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0006] Despite the emergence of various techniques in peptide-based therapeutics, there remains a need in the art for enzymatic systems for rapid and highly specific modification of a broad range of peptide and peptoid substances to obtain compound that are unattainable by traditional synthetic chemistry methods. These needs and others are addressed herein.SUMMARY

[0007] Provided herein are methods for chemically modifying a compound to install a thioether linkage, the method comprising reacting the compound with PapB. In some embodiments, the compound comprises one or more peptoid-based amino acid residue.

[0008] In one aspect the present technology relates to a method of chemically modifying a compound to install a thioether or a selenoether linkage, the method comprising reacting the compound with PapB, wherein the compound has a structure represented by a formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein t is selected from 1, 2, 3, 4, and 5;wherein A is S orSe;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein Z is *-NH(CH2CH2O)uCH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein u is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1 -C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, 01 -C4 alkoxy, C1 -C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3and R7is independently a side chain of an amino acid; wherein each of R4aand R4bis independently selected from hydrogen and C1-C4 alkyl;wherein R5is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1°ynand CT %Hwherein each of R6and R8is independently a side chain of an amino acid; and wherein R9is selected from -C(O)OH, -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2.

[0009] In another aspect, the present technology relates to a method of chemically modifying a compound to install a thioether or a selenoether linkage, the method comprising reacting the compound with PapB, wherein the compound has a structure represented by a formula:wherein each of m, n, and 0 is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v', and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein v’ is selected from 1, 2, 3, and 4;wherein Z is *-NH(CH2CH2O)wCH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein w’ is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1', and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1 -C4 hydroxyalkyl, 01-04 haloalkoxy, 01 -04 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3, R7, and R11is independently a side chain of an amino acid; wherein each of R4aand R4b, when present, is independently selected from hydrogen and 01-04 alkyl;wherein R6is a side chain of an amino acid;wherein R10is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine; andwherein each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid.

[0010] In another aspect, the present technology relates to a thioether or selenoether compound prepared by a method described herein.

[0011] In still another aspect, the present technology relates to a thioether or selenoether compound having a structure represented by the formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein v is selected from 0, 1, 2, 3, and 4;wherein A is S or Se;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein Z is *-NH(CH2CH2O)uCH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein u is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1” is covalently bonded to R2, R2', and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1 -C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3and R7is independently a side chain of an amino acid; wherein each of R4aand R4bis independently selected from hydrogen and C1-C4 alkyl;wherein R5is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein each of R6and R8is independently a side chain of an amino acid; and wherein R9is selected from -C(O)OH, -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2.

[0012] In yet another aspect, the present technology relates to a thioether or selenoether compound having a structure represented by the formula:wherein each of m, n, and 0 is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v’, and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein v’ is selected from 1, 2, 3, and 4;wherein Z is *-NH(CH2CH2O)W’CH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein w’ is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1', and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1 -C4 hydroxyalkyl, 01-04 haloalkoxy, 01 -04 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3, R7, and R11is independently a side chain of an amino acid; wherein each of R4aand R4b, when present, is independently selected from hydrogen and 01-04 alkyl;wherein R6is a side chain of an amino acid;wherein R10is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine; andwherein each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 is a representative schematic showing depicitions of standard peptide and peptoid.

[0014] FIGS. 2A and 2B are representative schematics showing the proposed formation of thioethers by PapB of a peptoid by sidechain cross-links.

[0015] FIG. 3 is a representative schematic showing the proposed formation of thioethers by PapB of a peptoid by a C-terminal cross-link.

[0016] FIGS. 4A and 4B show representative proton nuclear magnetic resonance (1H NMR) spectra of exemplary acyclic peptoid GCXANZA (SEQ ID NO: 8), wherein X is sarcosine and Z is N-glutamate. FIG. 4A shows a full1H NMR spectra and FIG. 4B shows a1H NMR zoomed in on the relevant section.

[0017] FIGS. 5A and 5B show representative1H NMR spectra of exemplary acyclic peptoid YGCXANZA (SEQ ID NO: 11), wherein X is sarcosine and Z is N-glutamate. FIG.5A shows a full1H NMR spectra and FIG. 5B shows a1H NMR zoomed in on the relevant section.

[0018] FIG. 6 shows representative mass spectra of exemplary Peptoid 1 before and after crosslinking with PapB. Exemplary Peptoid 1 has the amino acid sequence LKQINVIAGVKEPIRAYGCXANZA (SEQ ID NO: 4), wherein X isSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 sarcosine and Z is N-Glu, before crosslinking and LKQINVIAGVKEPIRAYGC1XANZ1A (SEQ ID NO: 5), wherein a thioether crosslink extends from C1to Z1, after crosslinking with PapB.

[0019] FIG. 7 is a representative schematic showing the formation of a thioether sidechain crosslink on an exemplary peptoid by reaction with PapB.

[0020] FIGS. 8A-8C show representative1H NMR spectra of exemplary cyclic peptoid GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1. FIG. 8A shows a full1H NMR spectra, FIG. 8B shows a1H NMR zoomed in on the relevant section, and FIG. 8C shows a1H NMR spectra overlay of acyclic (bottom) and cyclic (top) Peptoid 3.

[0021] FIGS. 9A-9D show representative1H NMR spectra of exemplary acyclic peptoid YGC1XANZ1A (SEQ ID NO: 13), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1. FIG. 9A shows a full1H NMR spectra, FIG. 9B shows a1H NMR zoomed in on the relevant section, FIG. 9C shows a variable temperature NMR spectra, and FIG. 9D shows a rotating frame Overhauser effect spectroscopy (ROESY) spectra.

[0022] FIG. 10 shows a representative mass spectra of the peptoid GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-Glu, a thioether crosslink extends from C1to Z1, after reaction with PapB and subsequent cleavage of the leader sequence.DETAILED DESCRIPTION

[0023] The present technology provides methods of installing intrapeptide thioether and selenoether linkages on compounds comprising one or more peptoid-based amino acid residues and thioether or selenoether compounds prepared by such methods. In some embodiments, the methods include reacting a peptide comprising one or more peptoid-based amino acid residues with PapB.

[0024] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the presentSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 technology disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0025] While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized, and that logical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps recited in any method or process, may be executed in any order and are not limited to the order presented. Moreover, any of the steps thereof may be outsourced to or performed by one or more third parties.Definitions

[0026] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0027] As used in the specification and in the claims, the term “comprising” can include the embodiments “consisting of” and “consisting essentially of.”

[0028] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0029] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0030] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0031] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0032] As used herein, the term “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0033] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0034] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0035] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0036] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0037] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad embodiment, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences ofSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain embodiments, unless expressly indicated to the contrary, individual substituents can be further optionally substituted ( / .e., further substituted or unsubstituted).

[0038] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0039] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain ( / .e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0040] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, f-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl,SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0041] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, eg., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0042] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0043] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group asSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfooxo, or thiol as described herein.

[0044] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as — OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA1— OA2or — OA1— (OA2)a— OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0045] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0046] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carboncarbon double bound, / .e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0047] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0048] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carboncarbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0049] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized TT electrons above and below the plane of the molecule, where the TT clouds contain (4n+2) TT electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0050] The term “aryl” as used herein is a group that contains any carbonbased aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is aSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0051] The term “aldehyde” as used herein is represented by the formula — C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0052] The terms “amine” or “amino” as used herein are represented by the formula — NAW, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH2.

[0053] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0054] The term “dialkylamino” as used herein is represented by the formula — N(-alkyl)2 where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0055] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0056] The term “ester” as used herein is represented by the formula — OC(O)A1or — C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula — (A1O(O)C-A2-C(O)O)a— or — (A1O(O)C-A2-OC(O))a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0057] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0058] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0059] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0060] The term “heteroalkyl,” as used herein, refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0061] The term “heteroaryl,” as used herein, refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfooxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, A / -methylpyrrolyl,SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0062] The terms “heterocycle” or “heterocyclyl” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0063] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other thanSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a nonaromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1 H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0064] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0065] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[0066] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0067] The term “azide” or “azido” as used herein is represented by the formula — N3.

[0068] The term “nitro” as used herein is represented by the formula — NO2.

[0069] The term “nitrile” or “cyano” as used herein is represented by the formula —ON.

[0070] The term “silyl” as used herein is represented by the formula — SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0071] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)A1, — S(O)2A1, — OS(O)2A1, or — OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0072] The term “thiol” as used herein is represented by the formula — SH.

[0073] “R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant ( / .e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0074] As described herein, compounds of the technology may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this technology are preferably those thatSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain embodiments, unless expressly indicated to the contrary, individual substituents can be further optionally substituted ( / .e., further substituted or unsubstituted).

[0075] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0076] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)O-4R°, -0-(CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o-4N(R°)2; -(CH2)o-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(R°)C(0)NR02; -N(R°)C(S)NRO2; -(CH2)O-4N(R°)C(O)ORO; -N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(0)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)O-4C(0)R°; -C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; -(CH2)O- 4C(O)OSiR°3; -(CH2)O-40C(0)R°; -OC(0)(CH2)O-4SR-, SC(S)SR°; -(CH2)O-4SC(O)R°; -(CH2)O-4C(0)NR°2; -C(S)NRO2; -C(S)SR°; -(CH2)O-40C(0)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)o-4SSR0; -(CH2)O-4S(0)2R°; -(CH2)O-4S(0)20R°; -(CH2)O-40S(0)2R°; -S(O)2NRO2; -(CH2)O-4S(0)RO; -N(RO)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)2; or-(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CFhPh, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0077] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o-20H, -(CH2)o-20R*, -(CH2)o-2CH(OR*)2; -O(haloR’), -GN, -N3, -(CH2)o-2C(0)R*, -(CH2)o-2C(0)OH, -(CH2)o-2C(0)OR*, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR’s, -C(O)SR*, — (C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0078] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR‘, =NNHS(O)2R‘, =NR*, =NOR*, -O(C(R*2))2-3O- or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2- 3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0079] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR* -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0080] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rt, -NRt2, -C(O)Rt, -C(O)OR -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRt2, -C(NH)NRt2, or -N(Rt)S(O)2Rt;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein each Rfis independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rf, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0081] Suitable substituents on the aliphatic group of Rfare independently halogen, -R*, -(haloR*), -OH, -OR’, -O(haloR’), -GN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0082] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the technology includes all such possible isomers, as well as mixtures of such isomers.

[0083] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present technology includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0084] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically activeSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and I or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-lngold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0085] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemicalSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0086] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In some embodiments, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[0087] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S, S) / (R, R) and (R, S) / (S, R)). The pairs of enantiomers (e.g., (S, S) / (R, R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S, S) and (R, S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[0088] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di-, or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WOSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 2000 / 041531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[0089] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates. Examples of radio-actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.

[0090] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the technology include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36CI, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this technology. Certain isotopically-labeled compounds of the present technology, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred fortheir ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present technology and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0091] The compounds described in the technology can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds canSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the technology to form solvates and hydrates. Unless stated to the contrary, the technology includes all such possible solvates.

[0092] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.keto form enol form amide form imidic acid form

[0093] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, A / 1-unsubstituted, 3-A3and / \ / 1-unsubstituted, 5-A3as shown below.Unless stated to the contrary, the technology includes all such possible tautomers.

[0094] It is known that chemical substances form solids, which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the technology can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the technology includes all such possible polymorphic forms.

[0095] In some embodiments, a structure of a compound can be represented by a formula:which is understood to be equivalent to a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein n is typically an integer. That is, Rnis understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then R"(b)is not necessarily halogen in that instance.

[0096] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N. J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0097] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0098] Disclosed are the components to be used to prepare the compositions of the technology as well as the compositions themselves to be used within theSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all embodiments of this application including, but not limited to, steps in methods of making and using the compositions of the technology. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the technology.

[0099] It is understood that the compounds and compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.Compounds

[0100] In some embodiments, the present technology relates to compounds capable of being enzymatically modified via reaction with PapB in order to install one or more thioether or selenoether linkages. In further embodiments, the compounds of the present technology comprise a first amino acid capable of forming the intrapeptide thioether or selenoether linkage and a second amino acid capable of forming the intrapeptide thioether or selenoether linkage. In some embodiments, theSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 first amino acid capable of forming an intrapeptide thioether or selenoether linkage is a peptoid-based amino acid. In some embodiments, the second amino acid capable of forming an intrapeptide thioether or selenoether linkage is a peptoid-based amino acid. In some embodiments, the first and second amino acids capable of forming an intrapeptide thioether or selenoether linkage are each independently peptoid-based amino acids. As used herein, peptoid-based amino acids are referred to as N-amino acids, (e.g., N-glutamate).

[0101] In some embodiments, the first amino acid capable of forming an intrapeptide thioether or selenoether linkage is N-terminal to the second amino acid capable of forming an intrapeptide thioether or selenoether linkage.

[0102] In some embodiments, the first amino acid capable of forming an intrapeptide thioether or selenoether linkage is selected from cysteine, homocysteine, penicillamine, thiothreonine, selenocysteine, and homoselenocystine, and the second amino acid capable of forming an intrapeptide thioether or selenoether linkage is selected from aspartate, glutamate, homoglutamate, methylaspartate, and methylglutamate.

[0103] In some embodiments, the first amino acid capable of forming an intrapeptide thioether or selenoether linkage is selected from cysteine, homocysteine, penicillamine, thiothreonine, selenocysteine, and homoselenocystine, and the second amino acid capable of forming an intrapeptide thioether or selenoether linkage is a peptoid-based amino acid selected from N-glutamate, N-aspartate, and N-homoglutamate.

[0104] In some embodiments, the first amino acid capable of forming an intrapeptide thioether or selenoether linkage is a peptoid-based amino acid selected from N-cysteine, N-homocysteine, N-penicillamine, N-thiothreonine, N-selenocysteine, and N-homoselenocystine, and the second amino acid capable of forming an intrapeptide thioether or selenoether linkage is selected from aspartate, glutamate, homoglutamate, methylaspartate, and methylglutamate.

[0105] In some embodiments, the first amino acid capable of forming an intrapeptide thioether or selenoether linkage is a peptoid-based amino acid selected from N-cysteine, N-homocysteine, N-penicillamine, N-thiothreonine, N-selenocysteine, and N-homoselenocystine, and the second amino acid capable of forming an intrapeptide thioether or selenoether linkage is a peptoid-based amino acid selected from N-glutamate, N-aspartate, and N-homoglutamate.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0106] In some embodiments, the first amino acid capable of forming an intrapeptide thioether or selenoether linkage and the second amino acid capable of forming an intrapeptide thioether or selenoether linkage are adjacent or within 20 amino acids of each other. In further embodiments, the amino acids capable of forming an intrapeptide thioether or selenoether linkage are adjacent or within 15 amino acids of each other. In still further embodiments, the amino acids capable of forming an intrapeptide thioether or selenoether linkage are adjacent or within 10 amino acids of each other. In yet further embodiments, the amino acids capable of forming an intrapeptide thioether or selenoether linkage are adjacent or within 5 amino acids of each other. In further embodiments, the amino acids capable of forming an intrapeptide thioether or selenoether linkage are adjacent or within 3 amino acids of each other. In further embodiments, the amino acids capable of forming an intrapeptide thioether or selenoether linkage are adjacent or within 2 amino acids of each other.

[0107] It is contemplated that each disclosed compound can be optionally further substituted. It is also contemplated that any one or more compounds can be optionally omitted from the technology. It is understood that a disclosed compound can be provided by the disclosed methods.Structure

[0108] In some embodiments, disclosed are compounds having a structure represented by a formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1; wherein p is an integer selected from 0 to 50; wherein q is an integer selected from 0 to 20; wherein r is an integer selected from 0 to 500; wherein s is selected from 1 and 2; wherein t is selected from 1, 2, 3, 4, and 5; wherein A is S or Se; wherein Q1is a leader sequence; wherein Q2is a cleavable moiety; wherein Z is *-NH(CH2CH2O)uCH2C(O)-**; wherein * denotes a bondSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 connected to -Q2- and ** denotes a bond connected to the remainder of the compound; wherein u is selected from 1, 2, 3, 4, 5, and 6; wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid, or wherein R1, R1', or R1" is covalently bonded to R2, R2', and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle; wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R3and R7is independently a side chain of an amino acid; wherein each of R4aand R4bis independently selected from hydrogen and C1-C4 alkyl; wherein R5is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:wherein each of R6and R8is independently a side chain of an amino acid; and wherein R9is selected from -C(O)OH, -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2.

[0109] In some embodiments, disclosed are compounds having a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1; wherein p is an integer selected from 0 to 50; wherein q is an integer selected from 0 to 20; wherein r is an integer selected from 0 to 500; wherein s is selected from 1 and 2; wherein each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0; wherein A is S or Se; wherein Q1is a leader sequence; wherein Q2is a cleavable moiety; wherein L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v', and a structure selected from:wherein V is selected from 1, 2, 3, and 4; wherein Z is *-NH(CH2CH2O)WCH2C(O)-**; wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound; wherein w’ is selected from 1, 2, 3, 4, 5, and 6; wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid, or wherein R1, R1’, or R1’’ is covalently bonded to R2, R2”, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle; wherein Ar1selected from a 5-to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R3, R7, and R11is independently a side chainSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 of an amino acid; wherein each of R4aand R4b, when present, is independently selected from hydrogen and C1-C4 alkyl; wherein R6is a side chain of an amino acid; wherein R10is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, structure selected from:wherein R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine; and wherein each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid.

[0110] In some embodiments, the compound has a structure represented by a formula:

[0111] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0112] In some embodiments, the compound has a structure represented by a formula selected from:

[0113] In some embodiments, the compound has a structure represented by a formula:

[0114] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0115] In some embodiments, the compound has a structure represented by a formula:

[0116] In some embodiments, the compound has a structure represented by a formula:

[0117] In some embodiments, the compound has a structure represented by a formula:

[0118] In some embodiments, the compound has an amino acid sequence GCXANZA (SEQ ID NO: 7), wherein X is any amino acid and Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage. In furtherSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 embodiments, X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate. In still further embodiments, X is sarcosine and Z is N-glutamate.

[0119] In some embodiments, the compound has an amino acid sequence GCXANZA (SEQ ID NO: 8), wherein X is sarcosine and Z is N-glutamate.

[0120] In some embodiments, the compound has an amino acid sequence YGCXANZA (SEQ ID NO: 10), wherein X is any amino acid and Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage. In further embodiments, X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate. In still further embodiments, X is sarcosine and Z is N-glutamate.

[0121] In some embodiments, the compound has an amino acid sequence YGCXANZA (SEQ ID NO: 11), wherein X is sarcosine and Z is N-glutamate.

[0122] In some embodiments, the compound has a structure represented by a formula:

[0123] In some embodiments, the compound has a structure represented by a formula:

[0124] In some embodiments, the compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0125] In some embodiments, the compound has a structure represented by a formula:

[0126] In some embodiments, the compound has a structure represented by a formula:

[0127] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0128] In some embodiments, the compound has a structure represented by a formula selected from:

[0129] In some embodiments, the compound has a structure represented by a formula:

[0130] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0131] In some embodiments, the compound has a structure represented by a formula:

[0132] In some embodiments, the compound has a structure represented by a formula:

[0133] In some embodiments, the compound has a structure represented by a formula:

[0134] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G -419841 -WO BS Docket No. 21101.0490P1

[0135] In some embodiments, the compound has a structure represented by a formula:

[0136] In some embodiments, the compound has a structure represented by a formula:

[0137] In some embodiments, the compound has a structure represented by a formula:

[0138] In some embodiments, the compound has a structure represented by a formula:

[0139] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0140] In some embodiments, the compound has a structure represented by a formula:

[0141] In some embodiments, the compound has a structure represented by a formula:

[0142] In some embodiments, the compound has a structure represented by a formula:

[0143] In some embodiments, the compound comprises one or more D-amino acid residues. In some embodiments, the compound comprises one or more p-amino acid residues. In some embodiments, the compound comprises one or more N-methylated amino acid residues.

[0144] In some embodiments, each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1. In some embodiments, each of m, n, and o is 1. In some embodiments, each of m, n, and o is 0. In some embodiments, each of m and n is 1, and o is 0. In some embodiments, each of mSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 and n is 0, and o is 0. In some embodiments, each of m and n is 0, and o is 0. In some embodiments, each of m and n is 0, and o is 1.

[0145] In some embodiments, each of m and n is 0.

[0146] In some embodiments, m is 1.

[0147] In some embodiments, p is an integer selected from 0 to 50. In further embodiments, p is an integer selected from 0 to 45. In still further embodiments, p is an integer selected from 0 to 40. In yet further embodiments, p is an integer selected from 0 to 35. In further embodiments, p is an integer selected from 0 to 30. In still further embodiments, p is an integer selected from 0 to 25. In yet further embodiments, p is an integer selected from 0 to 20. In further embodiments, p is an integer selected from 0 to 15. In still further embodiments, p is an integer selected from 0 to 10. In yet further embodiments, p is selected from 0, 1, 2, 3, 4, 5, and 6. In further embodiments, p is selected from 0, 1, 2, 3, 4, and 5. In still further embodiments, p is selected from 0, 1, 2, 3, and 4. In yet further embodiments, p is selected from 0, 1, 2, and 3. In further embodiments, p is selected from 0, 1, and 2. In still further embodiments, p is selected from 0 and 1.

[0148] In some embodiments, q is an integer from 0 to 20. In further embodiments, q is an integer from q to 15. In still further embodiments, q is an integer from 0 to 10. In yet further embodiments, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. In further embodiments, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In still further embodiments, q is 0, 1, 2, 3, 4, 5, 6, or 7. In yet further embodiments, q is 0, 1, 2, 3, 4, 5, or 6. In further embodiments, q is 0, 1, 2, 3, 4, or 5. In still further embodiments, q is 0, 1, 2, 3, or 4. In yet further embodiments, q is 0, 1, 2, or 3. In further embodiments, q is 0, 1, or 2. In still further embodiments, q is 0 or 1.

[0149] In some embodiments, r is an integer from 0 to 500. In further embodiments, r is an integer from 0 to 250. In still further embodiments, r is an integer from 0 to 100. In yet further embodiments, r is an integer from 0 to 50. In further embodiments, r is an integer from 0 to 25. In still further embodiments, r is an integer from 0 to 10. In yet further embodiments, r is 0, 1, 2, 3, 4, or 5. In further embodiments, r is 0, 1, 2, or 3. In still further embodiments, r is 0 or 1. In yet further embodiments, r is 0.

[0150] In some embodiments, s is 1 or 2. In some embodiments, s is 1. In some embodiments, s is 2.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0151] In some embodiments, t is 1, 2, 3, 4, or 5. In still further embodiments, t is 1, 2, 3, or 4. In yet further embodiments, t is 1, 2, or 3. In further embodiments, t is 1, or 2. In still further embodiments, t is 1 or 2. In yet further embodiments, t is 1. In further embodiments, t is 2.

[0152] In some embodiments, u is selected from 1, 2, 3, 4, 5, and 6. In further embodiments, u is selected from 1, 2, 3, 4, and 5. In still further embodiments, u is selected from 1, 2, 3, and 4. In yet further embodiments, u is selected from 1, 2, and 3. In further embodiments, u is selected from 1, and 2. In still further embodiments, u is 1.

[0153] In some embodiments, each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0. In some embodiments, v is 1 and w is 1. In some embodiments, v is 0 and w is 1. In some embodiments, v is 1 and w is 0. In some embodiments, v is 0 and w is 0.

[0154] In some embodiments, v is selected from 0 and 1. In some embodiments, v is 1. In some embodiments, v is 0.

[0155] In some embodiments, each of r and v is 0.

[0156] In some embodiments, w is selected from 0 and 1. In some embodiments, w is 1. In some embodiments, w is 0.

[0157] In some embodiments, is 1, 2, 3, or 4. In further embodiments, \Z is 1, 2, or 3. In still further embodiments, v’ is 1 or 2. In yet further embodiments, v’ is 1.

[0158] In some embodiments, w’ is selected from 0, 1, 2, 3, 4, 5, and 6. In further embodiments, w’ is selected from 0, 1, 2, 3, 4, and 5. In still further embodiments, w’ is selected from 0, 1, 2, 3, and 4. In yet further embodiments, w’ is selected from 0, 1, 2, and 3. In further embodiments, w’ is selected from 0, 1, and 2. In still further embodiments, w’ is selected from 0 and 1.A Groups

[0159] In some embodiments, A is S or Se. In some embodiments, A is S. In some embodiments, A is Se.L Groups

[0160] In some embodiments, L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v’, and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0161] In some embodiments, L is selected from C2-C4 alkyl and -(C1-C4 alkyl)(OCH2CH2)v’. In further embodiments, L is selected from ethyl, n-propyl, isopropyl, -CH2(OCH2CH2)v, -CH2CH2(OCH2CH2)v’, -CH2CH2CH2(OCH2CH2)v', and -CH(CH3)(CH2(OCH2CH2)v). In still further embodiments, L is selected from ethyl, -CH2(OCH2CH2)v’, and -CH2CH2(OCH2CH2)v’. In yet further embodiments, L is -CH2(OCH2CH2)v'.

[0162] In some embodiments, L is a structure selected from:Q1Groups

[0163] In some embodiments, Q1is a leader sequence. In further embodiments, the leader sequence is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2). In yet further embodiments, the leader sequence is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).Q2Groups

[0164] In some embodiments, Q2is a cleavable moiety such as, for example, a chemically cleavable moiety or an enzymatically cleavable moiety.

[0165] In some embodiments, Q2is a chemically cleavable moiety. Exemplary chemical cleavable moieties include, but are not limited to, -CO2-(C4-C8 alkylene)-OC(O)-. In further embodiments, the chemically cleavable moiety is -CO2CH2CH=CHCH2OC(O)-.

[0166] In some embodiments, Q2is an enzymatically cleavable moiety such as, for example, a protease recognition sequence. In further embodiments, the protease recognition sequence is TEV recognition sequence. In further embodiments, the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 Z Groups

[0167] In some embodiments, Z is *-NH(CH2CH2O)uCH2C(O)-**; wherein * denotes a bond connected to -Q2-. In further embodiments, Z is selected from *-NH(CH2CH2O)CH2C(O)-**, *-NH(CH2CH2O)2CH2C(O)-**, *-NH(CH2CH2O)3CH2C(O)-**, and *-NH(CH2CH2O)4CH2C(O)-**. In still further embodiments, Z is *-NH(CH2CH2O)4CH2C(O)-**.

[0168] In some embodiments, Z is *-NH(CH2CH2O)wCH2C(O)-**; wherein * denotes a bond connected to -Q2-. In further embodiments, Z is selected from *-NH(CH2CH2O)CH2C(O)-**, *-NH(CH2CH2O)2CH2C(O)-**, *-NH(CH2CH2O)3CH2C(O)-**, and *-NH(CH2CH2O)4CH2C(O)-**. In still further embodiments, Z is *-NH(CH2CH2O)4CH2C(O)-**.R1, R1’, R1", R2, R2’, and R2’’and Groups

[0169] In some embodiments, each occurrence of R1, R1’, and R1", when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid, or wherein R1, R1', or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle.

[0170] In some embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1. In further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(CH3)CH2OH, -CH2SH, -CH2CH2SH, -CH2CH2CH2SH, -CH(CH3)CH2SH, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2SCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, -CH2SHCH2CH3, -CH2CH2SCH2CH3, -CH2CH2CH2SCH2CH3, -CH2SCH2H2CH3, CH2CH2SCH2H2CH3, -CH2CH2CH2SCH2H2CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2CH2CH2C(O)NH2, -CH2Ar1, -CH2CH2Ar1, -CH2CH2CH2Ar1, and Ar1. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, methyl, ethyl, -CH2OH, -CH2CH2OH, -CH2SH, -CH2CH2SH, -CH2NH2, -CH2CH2NH2, -CH2SCH3, -CH2CH2SCH3, -SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 CH2SHCH2CH3, -CH2CH2SCH2CH3, -CH2SCH2H2CH3, -CH2CH2SCH2H2CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2Ar1, -CH2CH2Ar1, and Ar1. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, methyl, -CH2OH, -CH2SH, -CH2NH2, -CH2SCH3, -CH2C(O)NH2, -CH2Ar1, and Ar1.

[0171] In some embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, -(C1-C4)Ar1, and Ar1. In further embodiments, each occurrence of R1, R1', and R1", when present, is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CFFAr1, -CH2CH2Ar1, -CH2CH2CH2Ar1, and Ar1. In still further embodiments, each occurrence of R1, R1’, and R1", when present, is independently selected from hydrogen, methyl, ethyl, -CH2Ar1, -CH2CH2Ar1, and Ar1. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, methyl, -CFFAr1, and Ar1.

[0172] In some embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 aminoalkyl, and -(C1-C4)C(O)NH2. In further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2C(O)NH2, -CH2CH2C(O)NH2, and -CH2CH2CH2C(O)NH2. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, -CH2NH2, -CH2CH2NH2, -CH2C(O)NH2, and -CH2CH2C(O)NH2. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, -CH2NH2, and-CH2C(O)NH2.

[0173] In some embodiments, each occurrence of R1, R1’, and R1", when present, is independently selected from hydrogen, C1-C4 alkylthiol, and -(C1-C4)S(C1-C4 alkyl). In further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, -CH2SH, -CH2CH2SH, -CH2CH2CH2SH, -CH(CH3)CH2SH, -CH2SCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, -CH2SHCH2CH3, -CH2CH2SCH2CH3, -CH2CH2CH2SCH2CH3, -CH2SCH2H2CH3, -CH2CH2SCH2H2CH3, and -CH2CH2CH2SCH2H2CH3. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, -CH2SH, -CH2CH2SH, -CH2SCH3, -CH2CH2SCH3, -CH2SHCH2CH3, -CH2CH2SCH2CH3, -CH2SCH2H2CH3, and -CH2CH2SCH2H2CH3. In still furtherSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, -CH2SH, and -CH2SCH3.

[0174] In some embodiments, each occurrence of R1, R1’, and R1", when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, -(C1-C4)C(O)NH2, and -(C1-C4)Ar1. In further embodiments, each occurrence of R1, R1', and R1”, when present, is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2CH2CH2C(O)NH2, -CH2Ar1, -CH2CH2Ar1, and -CH2CH2CH2Ar1. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, methyl, ethyl, -CH2NH2, -CH2CH2NH2, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2Ar1, and -CH2CH2Ar1. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, methyl, -CH2NH2, -CH2C(O)NH2, and -CH2Ar1.

[0175] In some embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen and C1-C4 alkyl. In further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In still further embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, methyl, and ethyl. In some embodiments, each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen and methyl.

[0176] In some embodiments, wherein at least one of R1', R1’, and R1”, when present, is not hydrogen.

[0177] In some embodiments, wherein each of R1, R1', and R1”, when present, is hydrogen,

[0178] In some embodiments, each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid.

[0179] Exemplary residues of a side chain of an amino acid include, but are not limited to, side chains of natural amino acid residues, unnatural amino acid residues, and D-amino acid residues. In some embodiments, at least one of R2, R2’, and R2” is a side chain of a D-amino acid residue. In some embodiments, at least one of R2, R2’, and R2” is a side chain of a p-amino acid residue. In some embodiments, at least one of R2, R2’, and R2”is a side chain of an N-methylated amino acid residue.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0180] Natural amino acid residues may include glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan, serine, cysteine, threonine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, histidine, and lysine.

[0181] Unnatural amino acid residues may include, but are not limited to, p-ethylthiocarbonyl-L-phenylalanine, p-(3-oxobutanoyl)-L-phenylalanine, 1,5-dansyl-alanine, 7-amino-coumarin amino acid, 7-hydroxy-coumarin amino acid, nitrobenzylserine, O-(2-nitrobenzyl)-L-tyrosine, p-carboxymethyl-L-phenylalanine, p-cyano-L-phenylalanine, m-cyano-L-phenylalanine, biphenylalanine, 3-amino-L-tyrosine, bipyridyl alanine, p-(2-amino-1-hydroxyethyl)-L-phenylalanine, p-isopropylthiocarbonyl-L-phenylalanine, 3-nitro-L-tyrosine p-nitro-L-phenylalanine, p-propargyloxyphenylalanine, 3,4-dihydroxy-L-phenyalanine (DHP), 3,4,6-trihydroxy-L-phenylalanine, 3,4,5-trihydroxy-L-phenylalanine, 4-nitro-phenylalanine, p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, L-3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, 3-nitro-tyrosine, 3-thiol-tyrosine, tri-O-acetyl-GIcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, and the like.

[0182] In some embodiments, each of R2, R2’, and R2", when present, is independently a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0183] In some embodiments, R1, R1', or R1” is covalently bonded to R2, R2', and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle.R3, R7, and R11Groups

[0184] In some embodiments, each of R3, R7, and R11is independently a side chain of an amino acid.

[0185] In some embodiments, each of R3and R7is independently a side chain of an amino acid.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0186] In some embodiments, each of R3, R7, and R11is not a glycine side chain.

[0187] In some embodiments, each of R3, R7, and R11is a glycine side chain.

[0188] In some embodiments, R3is a side chain of an amino acid selected from glycine, alanine, cysteine, homocysteine, and selenocysteine. In further embodiments, R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.

[0189] In some embodiments, R7is a side chain of an amino acid selected from glycine and alanine. In further embodiments, R7is an alanine side chain.

[0190] In some embodiments, each of R3and R7is not hydrogen.

[0191] In some embodiments, R11is a side chain of an amino acid selected from glycine and alanine. In further embodiments, R11is an alanine side chain.

[0192] In some embodiments, R11is not a glycine side chain.R4aand R4bGroups

[0193] In some embodiments, each of R4aand R4b, when present, is independently selected from hydrogen and C1-C4 alkyl. In further embodiments, each of R4aand R4b, when present, is independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In still further embodiments, each of R4aand R4b, when present, is independently selected from hydrogen, methyl, and ethyl. In yet further embodiments, each of R4aand R4b, when present, is independently selected from hydrogen and methyl.

[0194] In some embodiments, each of R4aand R4b, when present, is hydrogen. R5Groups

[0195] In some embodiments, R5is selected from -CO2H, -C(O)NHOH, -SO2NH2, -SO2NHC(O)CH3, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0196] In some embodiments, R5is selected from -CO2H, -C(O)NHOH, -SO2NH2, -SO2NHC(O)CH3, -SO3H, -NHC(O)NHSO2CH3, and -P(O)(OH)2. In further embodiments, R5is selected from -CO2H, -C(O)NHOH, -SO2NH2, and -SO2NHC(O)CH3. In still further embodiments, R5is selected from -CO2H and -C(O)NHOH. In yet further embodiments, R5is-CO2H.

[0197] In some embodiments, R5is a structure selected from:

[0198] In some embodiments, R5is -CO2H or a structure:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0199] In some embodiments, R5is a structure:HNvN=N

[0200] In some embodiments, R5is -CO2H.R6and R8Groups

[0201] In some embodiments, each of R6and R8is independently a side chain of an amino acid.

[0202] In some embodiments, R6is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0203] In some embodiments, R6is a glycine side chain.

[0204] In some embodiments, R8is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0205] In some embodiments, R8is an alanine side chain.R9Groups

[0206] In some embodiments, R9is selected from -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2. In further embodiments, R9is selected from -CH2OH, -CH2SH, and -CH2NH2. In still further embodiments, R9is selected from -CH2OH and -CH2SH. In yet further embodiments, R9is -CH2OH.

[0207] In some embodiments, R9is selected from -CH2NH2 and -C(O)NH2. In further embodiments, R9is -CH2NH2. In a still further aspsect, R9is -C(O)NH2. R10Groups

[0208] In some embodiments, R9is selected from -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2. In further embodiments, R9is selected from -CH2OH, -CH2SH, and -CH2NH2. In still further embodiments, R9is selected from -CH2OH and -CH2SH. In yet further embodiments, R9is -CH2OH.

[0209] In some embodiments, R9is selected from -CH2NH2 and -C(O)NH2. In further embodiments, R9is -CH2NH2. In a still further aspsect, R9is -C(O)NH2.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 R11Groups

[0210] In some embodiments, R9is selected from -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2. In further embodiments, R9is selected from -CH2OH, -CH2SH, and -CH2NH2. In still further embodiments, R9is selected from -CH2OH and -CH2SH. In yet further embodiments, R9is -CH2OH.

[0211] In some embodiments, R9is selected from -CH2NH2 and -C(O)NH2. In further embodiments, R9is -CH2NH2. In a still further aspsect, R9is -C(O)NH2. R12Groups

[0212] In some embodiments, R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine.

[0213] In some embodiments, R12is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan. In further embodiments, R12is a side chain of an amino acid selected from alanine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, and glycine. In still further embodiments, R12is a glycine side chainR13aand R13bGroups

[0214] In some embodiments, each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid. In further embodiments, each of R13aand R13bis independently selected from -CCH, -CH2CCH, -CH2CH2CCH, -CH2N3, -CH2CH2N3, -CH2CH2CH2N3, -CH2CH2CH2CH2N3, and a side chain of an amino acid. In still further embodiments, each of R13aand R13bis independently selected from -CCH, -CH2CCH, -CH2N3, -CH2CH2N3, and a side chain of an amino acid. In yet further embodiments, each of R13aand R13bis independently selected from -CCH, -CH2N3, and a side chain of an amino acid.

[0215] In some embodiments, each of R13aand R13bis independently selected from C2-C5 alkynyl and a side chain of an amino acid. In further embodiments, each of R13aand R13bis independently selected from -CCH, -CH2CCH, -CH2CH2CCH, and a side chain of an amino acid. In still further embodiments, each of R13aand R13bis independently selected from -CCH, -CH2CCH, and a side chain of an amino acid. In yet further embodiments, each of R13aand R13bis independently selected from -CCH and a side chain of an amino acid.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0216] In some embodiments, each of R13aand R13bis independently selected from C1-C5 azido and a side chain of an amino acid. In further embodiments, each of R13aand R13bis independently selected from -CH2N3, -CH2CH2N3, -CH2CH2CH2N3, -CH2CH2CH2CH2N3, and a side chain of an amino acid. In still further embodiments, each of R13aand R13bis independently selected from -CH2N3, -CH2CH2N3, -CH2CH2CH2N3, and a side chain of an amino acid. In yet further embodiments, each of R13aand R13bis independently selected from -CH2N3, -CH2CH2N3, and a side chain of an amino acid. In further embodiments, each of R13aand R13bis independently selected from -CH2N3 and a side chain of an amino acid.Ar1Groups

[0217] In some embodiments, Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In further embodiments, Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In still further embodiments, Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet further embodiments, Ar1is selected from a 5- to 10-membered heteroaryl and a 6-to 10-membered aryl, and is monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In further embodiments, Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0218] In some embodiments, Ar1is a 5- to 10-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of 5- to 10-membered heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, pyrazole, triazole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, pyrimidine, and pyrazine. In further embodiments, Ar1is a 5- to 10-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In still further embodiments, Ar1is a 5- to 10-membered heteroaryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet further embodiments, Ar1is a 5- to 10-membered heteroaryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In further embodiments, Ar1is an unsubstituted 5- to 10-membered heteroaryl.

[0219] In some embodiments, Ar1is a 6- to 10-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In further embodiments, Ar1is a 6- to 10-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In still further embodiments, Ar1is a 6- to 10-membered aryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet further embodiments, 6- to 10-SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 membered aryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In further embodiments, Ar1is an unsubstituted 6- to 10-membered aryl.

[0220] In some embodiments, Ar1is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In further embodiments, Ar1is a 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In still further embodiments, Ar1is a 6-membered aryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet further embodiments, Ar1is a 6-membered aryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In further embodiments, Ar1is an unsubstituted 6-membered aryl.Thioether or Selenoether Compounds

[0221] In some embodiments, disclosed are thioether or selenoether compounds produced by a disclosed method.

[0222] Thus, in some embodiments, the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein v is t-1.

[0223] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0224] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0225] In some embodiments, the thioether or selenoether compound has a structure represented by a formula selected from:

[0226] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0227] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0228] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0229] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0230] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0231] In some embodiments, the thioether or selenoether compound has an amino acid sequence GC1XANZ1A (SEQ ID NO: 9), wherein X is any amino acid, Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1. In further embodiments, X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate. In still further embodiments, X is sarcosine and Z is N-glutamate.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0232] In some embodiments, the thioether or selenoether compound has an amino acid sequence GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

[0233] In some embodiments, the thioether or selenoether compound has an amino acid sequence YGC1XANZ1A (SEQ ID NO: 12), wherein X is any amino acid, Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1. In further embodiments, X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate. In still further embodiments, X is sarcosine and Z is N-glutamate.

[0234] In some embodiments, the thioether or selenoether compound has an amino acid sequence YGC1XANZ1A (SEQ ID NO: 13), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

[0235] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0236] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0237] In some embodiments, the thioether or selenoether compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0238] In some embodiments, the thioether compound has a structure represented by a formula:

[0239] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0240] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0241] In some embodiments, the thioether or selenoether compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0242] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0243] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0244] In some embodiments, the thioether compound has a structure represented by a formula:

[0245] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0246] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0247] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0248] In some embodiments, the thioether compound has a structure represented by a formula:

[0249] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0250] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0251] In some embodiments, the thioether compound has a structure represented by a formula:

[0252] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0253] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0254] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0255] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0256] In some embodiments, the thioether compound has a structure represented by a formula:

[0257] In some embodiments, the thioether compound has a structure represented by a formula:Methods of Chemically Modifying a Compound

[0258] In some embodiments, disclosed are methods of chemically modifying a compound to install a thioether or selenoether linkage, the method comprisingSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 reacting the compound with PapB, wherein the compound has a structure represented by a formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1; wherein p is an integer selected from 0 to 50; wherein q is an integer selected from 0 to 20; wherein r is an integer selected from 0 to 500; wherein s is selected from 1 and 2; wherein t is selected from 1, 2, 3, 4, and 5; wherein A is S or Se; wherein Q1is a leader sequence; wherein Q2is a cleavable moiety; wherein Z is *-NH(CH2CH2O)uCH2C(O)-**; wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound; wherein u is selected from 1, 2, 3, 4, 5, and 6; wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid, or wherein R1, R1’, or R1” is covalently bonded to R2, R2', and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle; wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1 -C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R3and R7is independently a side chain of an amino acid; wherein each of R4aand R4bis independently selected from hydrogen and 01-04 alkyl; wherein R5is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein each of R6and R8is independently a side chain of an amino acid; and wherein R9is selected from -C(O)OH, -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2.

[0259] Also disclosed are methods of chemically modifying a compound to install a thioether or selenoether linkage, the method comprising reacting the compound with PapB, wherein the compound has a structure represented by a formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1; wherein p is an integer selected from 0 to 50; wherein q is an integer selected from 0 to 20; wherein r is an integer selected from 0 to 500; wherein s is selected from 1 and 2; wherein each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0; wherein A is S or Se; wherein Q1is a leader sequence; wherein Q2is a cleavable moiety; wherein L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v', and a structure selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein V is selected from 1, 2, 3, and 4; wherein Z is *-NH(CH2CH2O)WCH2C(O)-**; wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound; wherein w’ is selected from 1, 2, 3, 4, 5, and 6; wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(01-C4)Ar1, and Ar1and wherein each occurrence of R2, R2', and R2”, when present, is independently a side chain of an amino acid, or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle; wherein Ar1selected from a 5-to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, 01-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, 01 -C4 hydroxyalkyl, C1-C4 haloalkoxy, 01-04 alkoxy, 01-04 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein each of R3, R7, and R11is independently a side chain of an amino acid; wherein each of R4aand R4b, when present, is independently selected from hydrogen and C1-C4 alkyl; wherein R6is a side chain of an amino acid; wherein R10is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3,SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine; and wherein each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid.

[0260] In some embodiments, each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1. In some embodiments, each of m, n, and o is 1. In still further embodiments, each of m, n, and o is 0. In some embodiments, each of m and n is 1, and o is 0. In some embodiments, each of m and n is 0, and o is 0. In some embodiments, each of m and n is 0, and o is 0. In some embodiments, each of m and n is 0, and o is 1.

[0261] In some embodiments, each of m and n is 0.

[0262] In some embodiments, m is 1.

[0263] In some embodiments, p is an integer selected from 0 to 50. In further embodiments, p is an integer selected from 0 to 45. In still further embodiments, p is an integer selected from 0 to 40. In yet further embodiments, p is an integer selected from 0 to 35. In further embodiments, p is an integer selected from 0 to 30. In still further embodiments, p is an integer selected from 0 to 25. In yet further embodiments, p is an integer selected from 0 to 20. In further embodiments, p is an integer selected from 0 to 15. In still further embodiments, p is an integer selected from 0 to 10. In yet further embodiments, p is selected from 0, 1, 2, 3, 4, 5, and 6. In further embodiments, p is selected from 0, 1, 2, 3, 4, and 5. In still further embodiments, p is selected from 0, 1, 2, 3, and 4. In yet further embodiments, p is selected from 0, 1, 2, and 3. In further embodiments, p is selected from 0, 1, and 2. In still further embodiments, p is selected from 0 and 1.

[0264] In some embodiments, q is an integer from 0 to 20. In further embodiments, q is an integer from q to 15. In still further embodiments, q is an integer from 0 to 10. In yet further embodiments, q is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. In further embodiments, q is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In still further embodiments, q is 0, 1, 2, 3, 4, 5, 6, or 7. In yet further embodiments, q is 0, 1, 2, 3, 4, 5, or 6. In further embodiments, q is 0, 1, 2, 3, 4, or 5. In still further embodiments, q is 0, 1, 2,SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 3, or 4. In yet further embodiments, q is 0, 1, 2, or 3. In further embodiments, q is 0, 1, or 2. In still further embodiments, q is 0 or 1.

[0265] In some embodiments, r is an integer from 0 to 500. In further embodiments, r is an integer from 0 to 250. In still further embodiments, r is an integer from 0 to 100. In yet further embodiments, r is an integer from 0 to 50. In further embodiments, r is an integer from 0 to 25. In still further embodiments, r is an integer from 0 to 10. In yet further embodiments, r is 0, 1, 2, 3, 4, or 5. In further embodiments, r is 0, 1, 2, or 3. In still further embodiments, r is 0 or 1. In yet further embodiments, r is 0.

[0266] In some embodiments, s is 1 or 2. In some embodiments, s is 1. In some embodiments, s is 2.

[0267] In some embodiments, t is 1, 2, 3, 4, or 5. In still further embodiments, t is 1, 2, 3, or 4. In yet further embodiments, t is 1, 2, or 3. In further embodiments, t is 1, or 2. In still further embodiments, t is 1 or 2. In yet further embodiments, t is 1. In further embodiments, t is 2.

[0268] In some embodiments, u is selected from 1, 2, 3, 4, 5, and 6. In further embodiments, u is selected from 1, 2, 3, 4, and 5. In still further embodiments, u is selected from 1, 2, 3, and 4. In yet further embodiments, u is selected from 1, 2, and 3. In further embodiments, u is selected from 1, and 2. In still further embodiments, u is 1

[0269] In some embodiments, each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0. In further embodiments, v is 1 and w is 1. In some embodiments, v is 0 and w is 1. In yet further embodiments, v is 1 and w is 0. In some embodiments, v is 0 and w is 0.

[0270] In some embodiments, v is selected from 0 and 1. In some embodiments, v is 1. In some embodiments, v is 0.

[0271] In some embodiments, each of r and v is 0.

[0272] In some embodiments, w is selected from 0 and 1. In some embodiments, w is 1. In some embodiments, w is 0.

[0273] In some embodiments, v” is 1, 2, 3, or 4. In further embodiments, is 1, 2, or 3. In still further embodiments, v’ is 1 or 2. In yet further embodiments, v’ is 1.

[0274] In some embodiments, R1is -CO2H or a structure:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0275] In some embodiments, R1is-CO2H.

[0276] In some embodiments, the cleavable moiety is a chemically cleavable moiety. Exemplary chemical cleavable moieties include, but are not limited to, -CO2-(C4-C8 alkylene)-OC(O)-. In further embodiments, the chemically cleavable moiety is -CO2CH2CH=CHCH2OC(O)-.

[0277] In some embodiments, the cleavable moiety is an enzymatically cleavable moiety such as, for example, a protease recognition sequence. In further embodiments, the protease recognition sequence is TEV recognition sequence.

[0278] In some embodiments, the compound comprises one or more D-amino acid residues. In some embodiments, the compound comprises one or more p-amino acid residues. In some embodiments, the compound comprises one or more N-methylated amino acid residues.

[0279] In some embodiments, PapB installs a single thioether or selenoether linkage in the compound. In some embodiments, PapB installs two or more thioether or selenoether linkages in the compound.

[0280] In some embodiments, the compound has a structure represented by a formula:

[0281] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0282] In some embodiments, the compound has a structure represented by a formula selected from:

[0283] In some embodiments, the compound has a structure represented by a formula:

[0284] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0285] In some embodiments, the compound has a structure represented by a formula:

[0286] In some embodiments, the compound has a structure represented by a formula:

[0287] In some embodiments, the compound has a structure represented by a formula:

[0288] In some embodiments, the compound has an amino acid sequence GCXANZA (SEQ ID NO: 7), wherein X is any amino acid and Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage. In furtherSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 embodiments, X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate. In still further embodiments, X is sarcosine and Z is N-glutamate.

[0289] In some embodiments, the compound has an amino acid sequence GCXANZA (SEQ ID NO: 8), wherein X is sarcosine and Z is N-glutamate.

[0290] In some embodiments, the compound has an amino acid sequence YGCXANZA (SEQ ID NO: 10), wherein X is any amino acid and Z is a peptoid-based amino acid residue capable of forming an intrapeptide thioether linkage. In further embodiments, X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate. In still further embodiments, X is sarcosine and Z is N-glutamate.

[0291] In some embodiments, the compound has an amino acid sequence YGCXANZA (SEQ ID NO: 11), wherein X is sarcosine and Z is N-glutamate.

[0292] In some embodiments, the compound has a structure represented by a formula:

[0293] In some embodiments, the compound has a structure represented by a formula:

[0294] In some embodiments, the compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0295] In some embodiments, the compound has a structure represented by a formula:

[0296] In some embodiments, the compound has a structure represented by a formula:

[0297] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0298] In some embodiments, the compound has a structure represented by a formula selected from:

[0299] In some embodiments, the compound has a structure represented by a formula:

[0300] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0301] In some embodiments, the compound has a structure represented by a formula:

[0302] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:wherein v is t-1.

[0303] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0304] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0305] In some embodiments, the thioether or selenoether compound has a structure represented by a formula selected from:

[0306] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0307] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0308] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0309] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0310] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0311] In some embodiments, the thioether or selenoether compound has an amino acid sequence GC1XANZ1A (SEQ ID NO: 9), wherein X is any amino acid, Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1. In further embodiments, X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate. In still further embodiments, X is sarcosine and Z is N-glutamate.

[0312] In some embodiments, the thioether or selenoether compound has an amino acid sequence GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

[0313] In some embodiments, the thioether or selenoether compound has an amino acid sequence YGC1XANZ1A (SEQ ID NO: 12), wherein X is any amino acid, Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1. In further embodiments, X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate. In still further embodiments, X is sarcosine and Z is N-glutamate.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0314] In some embodiments, the thioether or selenoether compound has an amino acid sequence YGC1XANZ1A (SEQ ID NO: 13), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

[0315] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0316] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0317] In some embodiments, the thioether or selenoether compound has a structure represented by a formula selected from:

[0318] In some embodiments, the thioether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0319] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0320] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0321] In some embodiments, the thioether or selenoether compound has a structure represented by a formula selected from:

[0322] In some embodiments, the thioether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0323] In some embodiments, the compound has a structure represented by a formula:

[0324] In some embodiments, the compound has a structure represented by a formula:

[0325] In some embodiments, the compound has a structure represented by a formula:

[0326] In some embodiments, the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0327] In some embodiments, the compound has a structure represented by a formula:

[0328] In some embodiments, the compound has a structure represented by a formula:

[0329] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0330] In some embodiments, the thioether or selenoether compound has a

[0331] In some embodiments, the thioether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0332] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0333] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0334] In some embodiments, the method further comprises addition of a reducing agent. In further embodiments, the reducing agent comprises dithionite, flavodoxin, flavodoxin reductase, titanium citrate, reduced nicotinamide adenine dinucleotide phosphate, or any combination thereof.

[0335] In some embodiments, the method further comprises addition of a protease. In further embodiments, the protease is selected from a TEV protease, chymotrypsin, and trypsin.

[0336] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0337] In some embodiments, the thioether or selenoether compound has a structure represented by a formula:

[0338] In some embodiments, the thioether compound has a structure represented by a formula:

[0339] In some embodiments, the thioether compound has a structure represented by a formula:EXAMPLES

[0340] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made andSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 evaluated, and are intended to be purely exemplary of the technology and are not intended to limit the scope of what the inventors regard as their technology. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0341] The Examples are provided herein to illustrate the technology, and should not be construed as limiting the technology in any way. Examples are provided herein to illustrate the technology and should not be construed as limiting the technology in any way.Example 1: Synthesis of Variants

[0342] The exemplary compounds were synthesized on either a PS3 peptide synthesizer (Protein Technologies Inc.), a Prelude peptide synthesizer (Protein Technologies Inc.), or a Chorus peptide synthesizer (Protein Technologies Inc.). The syntheses used standard Fmoc procedures from the manufacturer and were carried out on a 0.025 mmol scale. All natural Fmoc-amino acids were purchased from Protein Technologies Inc. The following unnatural amino acids were used in various syntheses: Fmoc-Sar-OH was purchased from Ambeed (A242282) and N-(Carboxymethyl)-N-Fmoc-b-alanine tert-butyl ester (Fmoc N-Glu) was purchased from Ambeed (A735645). To generate C-terminal carboxylate residues on the final peptide, 150 mg of 2-chlorotrityl chloride resin 100-200 mesh (ChemPep) was loaded with 0.03 mmol of Fmoc-protected amino acid (~0.2 mmol / g resin). The resin was washed three times with 5 mL DMF and three times with 5 mL dichloromethane (DCM). The 0.03 mmol of Fmoc-protected amino acid was dissolved in 1 mL of 1:1 dichloromethane (DCM): N, N-dimethylformaide (DMF) with 0.15 mmol diisopropylethylamine (DIPEA). This solution was added to the resin and gently shaken for 1 h. The Fmoc-Ala / DIPEA solution was then removed, and the resin was washed three times with 5 mL of DCM. The uncapped sites on the resin were capped by washing the resin with 20 mL of 17:2:1 DCM:methanol: DIPEA. The resin was then washed three times with 5 mL of DCM and three times with 5 mL of DMF. The resin was then transferred to the reaction vessel.Exemplary PeptoidsSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0343] Peptoid 1, having the amino acid sequence LKQINVIAGVKEPIRAYGCXANZA (SEQ ID NO: 4), Peptoid 2, having the amino acid sequence GCXANZA (SEQ ID NO: 8), and Peptoid 3, having the amino acid sequence YGCXANZA (SEQ ID NO: 11), wherein X is sarcosine and Z is N-Glu, was prepared according to the following protocol. The C-terminal Ala residue was loaded onto the 2-chlorotrityl chloride resin as described previously. Peptide elongation proceeded using standard solid-phase peptide synthesis (SPPS) protocols with Fmoc-protected amino acids. All natural Fmoc-amino acids (0.15 mmol, 6 equivalents) were activated in situ using N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU) (0.15 mmol, 6 equivalents; P3bioSystems, #31006) in 0.6 M N-methylmorpholine (NMM). Each elongation cycle followed the standard procedure: (1) 2 mL of DMF top wash; (2) 1.5 mL of 20% piperidine in DMF, incubated for 3 minutes with shaking and nitrogen gas, repeated twice; (3) 2 mL of DMF top wash, repeated six times; (4) addition of the amino acid, HATU activator, and NMM, followed by a 7-minute incubation with shaking and nitrogen gas; (5) 2 mL of DMF top wash, repeated six times. Unnatural amino acids, including Fmoc-Sar-OH (sarcosine) and N-(Carboxymethyl)-N-Fmoc-b-alanine tert-butyl ester (Fmoc N-Glu), were incorporated using the same elongation procedure but employed one-shot amino acid additions. The corresponding amino acid (50 mg) was dissolved in 1.5 mL of DMF, and the entire solution was introduced to the reaction vessel during the amino acid building block step. Following chain elongation, the N-terminal amino acid underwent an additional deprotection step in 20% piperidine to remove the Fmoc group. Peptide cleavage from the resin and simultaneous side-chain deprotection were performed using a cleavage cocktail of 87.5% trifluoroacetic acid (TFA), 5% thioanisole, 3% ethane dithiol, 2.5% triisopropylsilaane, and 2% anisole at 40 degrees C for 1 hours. The crude peptide was precipitated with cold diethyl ether and pelleted by centrifugation at 4,000 rpm for 10 minutes. The resulting solid was redissolved in water and lyophilized to yield the crude product. The crude peptide was purified by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) using a C18 column with a gradient of 5-55% acetonitrile in water (0.1% TFA) over 45 minutes at a flow rate of 5 mL / min. Purified fractions were pooled and lyophilized. The final product was characterized by HPLC-HRMS to confirm purity (>95%) and identity.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0344] Proton NMR (1H NMR) spectra were obtained for acyclic Peptoids 2 and 3 (FIGS. 4A-4B and 5A-5B, respectively). Chromatographic separation of the peptoid rotamers by HPLC was not achievable, so the NMR spectra were acquired and reported as a mixture. Extensive signal overlap precluded accurate determination of the rotamer distribution.

[0345] Acyclic Peptoid 2:1H NMR (800 MHz, D2O): (mixture of rotamers) 5 5.13 (dd, J = 8.1, 6.6 Hz, 0.6 H), 4.99 - 4.93 (m, 1H), 4.85 (dd, J = 8.3, 6.2 Hz, 1H), 4.74 (m, 1.5H), 4.33 (m, 0.7H), 4.29 - 4.19 (m, 2.5H), 4.19 - 4.14 (m, 0.5 H), 4.10 -4.00 (m, 1.5H), 3.99 - 3.92 (m, 1H), 3.77 (dd, J = 6.4, 3.1 Hz, 1.3H), 3.75 - 3.73 (m, 0.7H), 3.72 - 3.68 (t, J = 6.7 Hz, 1H), 3.56 (m, 0.5H), 3.44 (m, 0.5H), 3.10 (s, 2H), 3.09 (s, 1 H), 2.88 - 2.81 (m, 1.5H), 2.76 - 2.69 (m, 2H), 2.68 - 2.61 (m, 2H), 2.55 (dd, J= 15.6, 7.8 Hz, 1H), 2.50 (t, J = 6.7 Hz, 1H), 1.31 (d, J = 7.3 Hz, 1.3H), 1.29 (d, J = 7.3 Hz, 2H), 1.24 (d, J = 7.2 Hz, 1,7H), 1.22 (d, J = 7.2 Hz, 1 H).

[0346] Acyclic Peptoid 3:1H NMR (800 MHz, D2O) (mixture of rotamers) 5 7.11 - 6.90 (m, 2H), 6.83 - 6.59 (m, 2H), 5.23 - 5.04 (m, 0.5H), 4.89 (td, J = 6.4, 2.3 Hz, 0.7H), 4.83 (td, J = 6.6, 2.9 Hz, 0.5H), 4.40 - 4.28 (m, 0.5H), 4.27 - 4.21 (m, 1.5H), 4.21 - 4.14 (m, 1.5H), 4.12 (t, J = 7.2 Hz, 1H), 4.08 - 3.99 (m, 1.5H), 3.97 - 3.87 (m, 1.5H), 3.88 - 3.75 (m, 2H), 3.72 - 3.62 (m, 1H), 3.58 - 3.49 (m, 0.7H), 3.47 - 3.39 (m, 0.7H), 3.15 - 3.04 (m, 2H), 3.06 - 3.02 (m, 1H), 3.02 -2.96 (m, 1 H), 2.80 (dt, J = 10.0, 4.4 Hz, 1.5H), 2.77 - 2.68 (m, 2H), 2.67 - 2.60 (m, 2H), 2.58 - 2.51 (m, 1H), 2.49 (t, J= 6.2, 1H), 1.36 - 1.27 (m, 3H), 1.26 - 1.19 (m, 3H).Example 2: Enzymatic Reactions with PapB

[0347] Peptide variants, including Peptoids 1, 2, and 3, were subjected to reaction with PapB according to the following procedures. Assays were conducted in a Coy Laboratories anaerobic chamber with 98% N2 / 2% H2 atmosphere at room temperature. All reactions contained 0.05 M PIPES’NaOH (pH 7.4), 2mM DTT, 2.4 mM SAM (enzymatically synthesized and purified as previously described (deGruyter, J. N., et al. Biochem. 2017, 56 (30), 3863-3873)), -100 pM msPapA variants (concentration determined by peptide dry weight), and 5 pM PapB. Either dithionite (dT) orflavodoxin (FldA), flavodoxin reductase (FPR) and NADPH, or FMN with NADPH, were used to reduce PapB. For the assays that used chemical reductant, the total concentration was 2m M dT. For the assays that used the biological reducing system, the mixtures contained 25 pM FldA, 2 pM FPR and 2 mMSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 NADPH. Assays containing FMN and NADPH contained 55 uM and 2 mM respectively. The total volume of the reactions ranged from 0.1 mL for initial screenings to 0.5 mL for MS / MS Collision Induced Dissociation (CID) fragmentation experiments described below, or to 20 mLs to scale the reaction for receptor activation assays. Control reactions in the absence of PapB were also conducted. Reactions were initiated with the addition of PapB and quenched at times ranging from 2 h to 18 h by the addition of 10% of the reaction volume of 30% (w / v) trichloroacetic acid (TCA, ACS grade) or 2% of the reaction volume with 100% trifluoroacetic acid (TFA, ACS grade). The samples were centrifuged at 16,000 xg for 10 min in a microcentrifuge to pellet the precipitated PapB.Peptoid 1

[0348] Mass spectra analysis of cross-linking reaction of modified Peptoid 1 (LKQINVIAGVKEPIRAYGC1XANZ1A (SEQ ID NO: 5), wherein X is sarcosine and Z is N-Glu), comprising a thioether crosslink between cysteine and the C-terminal N-Glu residue was performed (FIG. 6). The expected monoisotopic mass of Peptoid 1 in the z=3 charge state is 843.4600, while the observed monoisotopic mass was 843.45888, resulting in a ppm error of -1.32. Following the reaction with PapB, a 2 Da shift was detected in the mass spectra, consistent with thioether bond formation. The expected monoisotopic mass of modified Peptoid 1 was 842.7881, with an observed monoisotopic mass of 842.78792, corresponding to a ppm error of -0.21. Additionally, reaction with iodoacetamide did not induce any mass shift, confirming that the sulfur of C19 was engaged in a thioether linkage rather than existing as a free thiol.Peptoids 2 and 3

[0349] Cross-linking of modified Peptoid 2 (GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine and Z is N-Glu), comprising a thioether crosslink between cysteine and the C-terminal N-Glu residue, was confirmed by mass spectra analysis. Table 1 shows expected and observed monoisotopic masses for various fragmentation patterns of Peptoid 2.Table 1. MS Fragmentation of Peptoid 2SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0350] Additionally, modification of Peptoids 2 and 3 to provide cyclized peptoids having sequences GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-Glu, and a thioether crosslink extends from C1to Z1and YGC1XANZ1A (SEQ ID NO: 13), wherein X is sarcosine, Z is N-Glu, and a thioether crosslink extends from C1to Z1was assessed by1H NMR analysis (FIGS. 8A-8C and 9A-9D). An exemplary schematic of the modifcation of acyclic Peptoid 3 to cyclic Peptoid 3 is provided in FIG. 7.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0351] Cyclic Peptoid 2:1H NMR (800 MHz, D2O) 5 4.58 - 4.50 (m, 2H), 4.41 (d, J= 18.1 Hz, 2H), 4.29 (d, J = 7.3 Hz, 2H), 4.17 (dd, J = 14.7, 3.5 Hz, 2H), 4.08 (d, J = 18.1 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.97 (d, J = 18.4 Hz, 2H), 3.72 (d, J = 1.5 Hz, 2H), 3.41 (dd, J = 9.5, 3.5 Hz, 1H), 3.02 (dd, J = 13.9, 7.2 Hz, 1H), 2.85 (s, 3H), 2.76 - 2.62 (m, 4H), 2.51 (dd, J = 14.9, 8.4 Hz, 1H), 1.33 (d, J= 7.3 Hz, 3H), 1.27 (d, J= 7.4 Hz, 3H).

[0352] Cyclic Peptoid 3:1H NMR (800 MHz, D2O) (major rotamer) 07.04 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 4.58 - 4.47 (m, 1 H), 4.37 (d, J = 17.8 Hz, 1 H), 4.22 (q, J = 7.0 Hz, 1 H), 4.11 (dt, J = 15.0, 5.5 Hz, 2H), 4.04 (dd, J = 14.7, 7.4 Hz, 1.4H), 3.96 (d, J = 18.5 Hz, 1H), 3.87 (d, J = 16.8 Hz, 1H), 3.69 (d, J = 17.0 Hz, 1H), 3.67 - 3.62 (m, 1.4H), 3.38 (dd, J = 10.2, 3.3 Hz, 1H), 3.14 (s, 0.5H), 3.02 (qd, J = 14.2, 7.3 Hz, 2H), 2.91 (dd, J = 13.7, 7.0 Hz, 1H), 2.84 (s, 2H), 2.73 (dd, J = 13.7, 4.5 Hz, 1H), 2.68 - 2.61 (m, 1H), 2.49 (dd, J = 14.8, 8.4 Hz, 0.7H), 1.29 (d, J = 7.3 Hz, 3H), 1.26 (d, J= 7.3 Hz, 3H).

[0353] As shown in the1H NMR spectra overlay of acylic (bottom) and cyclic (top) Peptoid 2 (SEQ ID NOs: 7 and 6, respectively) reaction with PapB successfully cyclized Peptoid 2 via a thioether crosslink (FIG. 8C). As will be appreciated by those skilled in the art, a diagnostic spectroscopic signature of ring closure is the behavior of the geminal methylene protons of the cysteine 0-CH2and the N-substituted glycine N-CH2groups. In the linear peptide, rapid conformational averaging about the flexible backbone renders these geminal proton pairs effectively enantiotopic, producing overlapping or near-degenerate signals. Upon macrocyclization, however, the conformational rigidity imposed by the thioether bridge breaks the local symmetry at these methylene centers, converting the enantiotopic protons into diastereotopic pairs that reside in chemically and magnetically distinct environments. As a result, these protons appear as two well-resolved, non-equivalent resonances in the spectrum of the cyclic peptide, a hallmark of restricted ring dynamics. This observation is further corroborated by significant chemical shift perturbations in the region (5 2.5 - 3.5 ppm) and by the overall sharpening and redistribution of aliphatic resonances.

[0354] The conformation of cyclic Peptoid 3 (SEQ ID NO: 13) was assessed using variable temperature1H NMR (VT-NMR) and rotating-frame Overhauser effect spectroscopy (ROESY). Specifically, VT-NMR spectroscopy was used to investigate the conformational dynamics of the Peptoid 3 in solution (FIG. 9C). As shown in FIG.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 8C, at 25 °C, the1H NMR spectrum displays two distinct sets of resonances for several backbone and side-chain protons, particularly in the aliphatic region (6 1.0-1.6 ppm), indicative of the presence of two interconverting rotameric species in slow exchange on the NMR timescale. This rotamerism originates from restricted rotation about the tertiary amide bond of the N-substituted glycine residue, where the partial double-bond character of the amide bond gives rise to distinct cis and trans conformational isomers. As the temperature was progressively increased from 25 °C to 70 °C, the two sets of signals gradually coalesced into a single set of sharp, well-resolved resonances, consistent with acceleration of the rotameric interconversion rate beyond the NMR timescale. The coalescence behavior observed between 40 °C and 60 °C indicates that the energy barrier to rotation about the N-methylamide bond is sufficient to render the two rotamers distinct species at ambient temperature, yet surmountable at elevated temperatures. These findings suggest that the macrocyclic scaffold populates two rotameric conformations in slow exchange at room temperature.

[0355] Additionally, the solution-state three-dimensional structure of the macrocyclic peptide was further investigated by ROESY (FIG. 9D). The ROESY spectrum of the cyclized product shows a network of through-space nuclear Overhauser effect (NOE) correlations, providing direct evidence for a well-defined and compact macrocyclic conformation in solution. The ROE cross-peaks observed between the cysteine p-CH2protons (5 -2.96 ppm) and the a-CH proton peptiod residue (6 -4.02 ppm) confirm the spatial proximity imposed by the covalent thioether bridge, consistent with the expected ring geometry of the macrocycle.Example 3: Chymotrypsin Cleavage of Peptides

[0356] Where proteolytic cleavage was necessary, e.g., Peptoid 1, 1 mg of chymotrypsin was added to the filtrate of a PapB assay that had been been centrifuged (4000 xg, 20 minutes) in an Amicon Ultra-15 centrifugal filter in a 1:1 volume ratio. The TEV-assay combination incuated for 2 h at 37 degrees C before quenching by the addition of 10% of the reaction volume of 30% (w / v) TCA or 2% of the reaction volume of 100% TEA. The samples were then centrifuged at 16,000 xg for 10 min in a microcentrifuge to pellet the precipitated TEV protease.

[0357] Mass spectra analysis of post chymotrypsin cleavage was conducted to verify cleavage of modified peptoids. FIG. 10 shows representative spectra ofSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 exemplary modified Peptoid 1 after cleavage. Chymotrypsin cleavage of the peptide liberated the macrocyclized core from the leader sequence, producing a cross-linked peptide with a sequence of GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-Glu, and a thioether crosslink extends from C1to Z1. The expected cross-linked monoisotopic mass of this peptide is 633.2297, the observed monoisoptopic mass was 633.22959, and the ppm error was -0.17. Addition of iodoacetamide did not alkylate this peptide, giving further evidence that the Cys residue is participating in a thioether bond.Additional Embodiments

[0358] Various embodiments of the present technology are set forth below in paragraphs

[0359] to

[0643] :

[0359] 1. A method of chemically modifying a compound to install a thioether or a selenoether linkage, the method comprising reacting the compound with PapB, wherein the compound has a structure represented by a formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein t is selected from 1, 2, 3, 4, and 5;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein Z is *-NH(CH2CH2O)uCH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein u is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1', or R1’’ is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3and R7is independently a side chain of an amino acid; wherein each of R4aand R4bis independently selected from hydrogen and 01-C4 alkyl;wherein R5is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3,wherein each of R6and R8is independently a side chain of an amino acid; andwherein R9is selected from -C(O)OH, -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0360] 2. The method of embodiment 1, wherein each of m and n is 0.

[0361] 3. The method of embodiment 1, wherein m is 1.

[0362] 4. The method of any one of embodiments 1-3, wherein o is 0.

[0363] 5. The method of any one of embodiments 1-3, wherein o is 1.

[0364] 6. The method of any one of embodiments 1-5, wherein p is an integer from 0 to 25.

[0365] 7. The method of any one of embodiments 1-6, wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0366] 8. The method of any one of embodiments 1-7, wherein p is selected from 0 and 1.

[0367] 9. The method of any one of embodiments 1-8, wherein r is 0.

[0368] 10. The method of any one of embodiments 1-9, wherein s is 1.

[0369] 11. The method of any one of embodiments 1-10, wherein A is S.

[0370] 12. The method of any one of embodiments 1-11, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2).

[0371] 13. The method of any one of embodiments 1-12, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).

[0372] 14. The method of any one of embodiments 1-13, wherein Q2is *-CO2-(C4-C8 alkylene)-OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

[0373] 15. The method of any one of embodiments 1-14, wherein Q2is *-CO2CH2CH=CHCH2OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

[0374] 16. The method of any one of embodiments 1-15, wherein Q2 is a chemically cleavable moiety.

[0375] 17. The method of embodiment 16, wherein the chemically cleavable moiety is a protease recognition sequence.

[0376] 18. The method of embodiment 17, wherein the protease recognition sequence is a TEV recognition sequence.

[0377] 19. The method of embodiment 18, wherein the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0378] 20. The method of any one of embodiments 1-19, wherein each of R1', R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, -(C1-C4)C(O)NH2, and -(C1-C4)Ar1.

[0379] 21. The method of any one of embodiments 1-19, wherein at least one of R1', R1’, and R1”, when present, is not hydrogen.

[0380] 22. The method of any one of embodiments 1-20, wherein each of R1, R1’, and R1”, when present, is hydrogen.

[0381] 23. The method of any one of embodiments 1-22, wherein each of R2, R2’, and R2”, when present, is independently a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0382] 24. The method of any one of embodiments 1-23, wherein R3is a side chain of an amino acid selected from glycine, alanine, cysteine, homocysteine, and selenocysteine.

[0383] 25. The method of any one of embodiments 1-24, wherein R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.

[0384] 26. The method of any one of embodiments 1-25, wherein each of R3and R7is not hydrogen.

[0385] 27. The method of any one of embodiments 1-26, wherein each of R4aand R4bis hydrogen.

[0386] 28. The method of any one of embodiments 1-27, wherein R5is -CO2H or a structure:

[0387] 29. The method of any one of embodiments 1-27, wherein R5is -CO2H.

[0388] 30. The method of any one of embodiments 1-29, wherein R6is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0389] 31. The method of any one of embodiments 1-30, wherein R6is a glycine side chain.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0390] 32. The method of any one of embodiments 1-31, wherein R7is a side chain of an amino acid selected from glycine and alanine.

[0391] 33. The method of any one of embodiments 1-32, wherein R7is an alanine side chain.

[0392] 34. The method of any one of embodiments 1-33, wherein R8is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, phenylalanine, tyrosine, and tryptophan.

[0393] 35. The method of any one of embodiments 1-34, wherein R8is an alanine side chain.

[0394] 36. The method of any one of embodiments 1-35, wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.

[0395] 37. The method of any one of embodiments 1-36, wherein Ar1is an unsubstituted 6-membered aryl.

[0396] 38. The method of any one of embodiments 1-37, wherein the compound comprises one or more D-amino acid residues.

[0397] 39. The method of any one of embodiments 1-38, wherein the compound comprises one or more p-amino acid residues.

[0398] 40. The method of any one of embodiments 1-39, wherein the compound comprises one or more N-methylated amino acid residues.

[0399] 41. The method of any one of embodiments 1-40, wherein PapB installs a single thioether linkage in the compound.

[0400] 42. The method of any one of embodiments 1-40, wherein PapB installs two or more thioether linkages in the compound.

[0401] 43. The method of any one of embodiments 1-42, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0402] 44. The method of any one of embodiments 1-43, wherein the compound has a structure represented by a formula:

[0403] 45. The method of any one of embodiments 1-43, wherein the compound has a structure represented by a formula selected from:

[0404] 46. The method of any one of embodiments 1-43, wherein the compound has a structure represented by a formula:

[0405] 47. The method of any one of embodiments 1-43, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0406] 48. The method of any one of embodiments 1-44 and 47, wherein the compound has a structure represented by a formula:

[0407] 49. The method of any one of embodiments 1-43, 46, and 47, wherein the compound has a structure represented by a formula:

[0408] 50. The method of any one of embodiments 1-44, 46, and 47, wherein the compound has a structure represented by a formula:

[0409] 51. The method of any one of embodiments 1-44 and 46-50, wherein the compound comprises an amino acid sequence GCXANZA (SEQ ID NO:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 7), wherein X is any amino acid and Z is a peptoid-based amino acid capable of forming a intrapeptide thioether linkage.

[0410] 52. The method of any one of embodiments 1-44 and 46-50, wherein the compound comprises an amino acid sequence YGCXANZA (SEQ ID NO: 10), wherein X is any amino acid and Z is a peptoid-based amino acid capable of forming a intrapeptide thioether linkage.

[0411] 53. The method of embodiment 51 or 52, wherein X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate.

[0412] 54. The method of any one of embodiments 51 and 53, wherein X is sarcosine and Z is from N-glutamate.

[0413] 55. The method of any one of embodiments 1-44, 46-51, 53, and 54, wherein the compound comprises an amino acid sequence GCXANZA (SEQ ID NO: 8), wherein X is sarcosine and Z is N-glutamate.

[0414] 56. The method of any one of embodiments 1-44, 46-50, and 52-54, wherein the compound comprises an amino acid sequence YGCXANZA (SEQ ID NO: 11), wherein X is sarcosine and Z is N-glutamate.

[0415] 57. The method of any one of embodiments 1-42, wherein the compound has a structure represented by a formula:

[0416] 58. The method of any one of embodiments 1-42 and 57, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0417] 59. The method of any one of embodiments 1-42 and 57, wherein the compound has a structure represented by a formula selected from:

[0418] 60. The method of any one of embodiments 1-42 and 57, wherein the compound has a structure represented by a formula:

[0419] 61. The method of any one of embodiments 1-42 and 57, wherein the compound has a structure represented by a formula:

[0420] 62. The method of any one of embodiments 1-42, 57, and 61, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0421] 63. The method of any one of embodiments 1-42, 57, 61, and 62, wherein the compound has a structure represented by a formula selected from:

[0422] 64. The method of any one of embodiments 1-42, 57, and 61, wherein the compound has a structure represented by a formula:

[0423] 65. The method of any one of embodiments 1-42 and 57, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0424] 66. The method of any one of embodiments 1-42, 57, and 65, wherein the compound has a structure represented by a formula:

[0425] 67. The method of any one of embodiments 1-42, wherein the thioether or selenoether compound has a structure represented by a formula:wherein v is t-1.

[0426] 68. The method of any one of embodiments 1-43 and 67, wherein the thioether or selenoether compound has a structure represented by a formula:

[0427] 69. The method of any one of embodiments 1-44, 67, and 68, wherein the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0428] 70. The method of any one of embodiments 1-43, 45, 67, and 68, wherein the thioether or selenoether compound has a structure represented by a formula:

[0429] 71. The method of any one of embodiments 1-43 and 67, wherein the thioether or selenoether compound has a structure represented by a formula:

[0430] 72. The method of any one of embodiments 1-43 and 67, wherein the thioether or selenoether compound has a structure represented by a formula:

[0431] 73. The method of any one of embodiments 1-44, 47, 67, and 72, wherein the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0432] 74. The method of any one of embodiments 1-43, 46, 47, 67, and 72, wherein the thioether or selenoether compound has a structure represented by a formula:

[0433] 75. The method of any one of embodiments 1-44, 46, 47, 67, and 72, wherein the thioether or selenoether compound has a structure represented by a formula:

[0434] 76. The method of any one of embodiments 1-44, 46-50, 67-69, and 71-75, wherein the thioether or selenoether compound has an amino acid sequence GC1XANZ1A (SEQ ID NO: 9), wherein X is any amino acid, Z is a peptoid-based amino acid capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1.

[0435] 77. The method of any one of embodiments 1-44, 46-50, 67-69, and 71-75, wherein the thioether or selenoether compound has an amino acid sequence YGC1XANZ1A (SEQ ID NO: 12), wherein X is any amino acid, Z is a peptoid-based amino acid capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1.

[0436] 78. The method of any one of embodiments 1-44, 46-50, 67-69, and 71-77, wherein X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0437] 79. The method of any one of embodiments 1-44, 46-50, 67-69, and 71-78, wherein X is sarcosine and Z is N-glutamate.

[0438] 80. The method of any one of embodiments 1-44, 46-51, 53-55, 67- 69, 71-76, 78, and 79, wherein the thioether or selenoether compound has an amino acid sequence GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

[0439] 81. The method of any one of embodiments 1-44, 46-50, 52-54, 56, 67-69, 71-75, and 77-79, wherein the thioether or selenoether compound has an amino acid sequence YGC1XANZ1A (SEQ ID NO: 13), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

[0440] 82. The method of any one of embodiments 1-42 and 57, wherein the thioether or selenoether compound has a structure represented by a formula:

[0441] 83. The method of any one of embodiments 1-42, 57, 58, and 82, wherein the thioether or selenoether compound has a structure represented by a formula:

[0442] 84. The method of any one of embodiments 1-42, 57, 59, and 82, wherein the thioether or selenoether compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0443] 85. The method of any one of embodiments 1-42, 57, 60, and 82, wherein the thioether compound has a structure represented by a formula:

[0444] 86. The method of any one of embodiments 1-42, 57, 61, and 82, wherein the thioether or selenoether compound has a structure represented by a formula:

[0445] 87. The method of any one of embodiments 1-42, 57, 62, 82, and 86, wherein the thioether or selenoether compound has a structure represented by a formula:

[0446] 88. The method of any one of embodiments 1-42, 57, 62, 82, and 86, wherein the thioether compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0447] 89. The method of any one of embodiments 1-42, 57, and 82, wherein the thioether compound has a structure represented by a formula:

[0448] 90. The method of any one of embodiments 1-89, wherein the method further comprises adding a reducing agent.

[0449] 91. The method of embodiment 90, wherein the reducing agent comprises dithionite, flavodoxin, flavodoxin reductase, titanium citrate, reduced nicotinamide adenine dinucleotide phosphate, or any combination thereof.

[0450] 92. The method of any one of embodiments 1-91, wherein the method further comprises adding a protease.

[0451] 93. The method of any one of embodiments 1-92, wherein the method produces a thioether or selenoether compound having a structure represented by a formula:wherein v is t-1.

[0452] 94. The method of any one of embodiments 1-93, wherein the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0453] 95. The method of any one of embodiments 1-94, wherein the thioether compound has a structure represented by a formula:

[0454] 96. The method of any one of embodiments 1-94, wherein the thioether or selenoether compound has a structure represented by a formula:

[0455] 97. A thioether or selenoether compound produced by the method of any one of embodiments 1-96.

[0456] 98. A method of chemically modifying a compound to install a thioether or a selenoether linkage, the method comprising reacting the compound with PapB, wherein the compound has a structure represented by a formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein s is selected from 1 and 2;wherein each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v’, and a structure selected from:wherein V is selected from 1, 2, 3, and 4;wherein Z is *-NH(CH2CH2O)w'CH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein w’ is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1’’ is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3, R7, and R11is independently a side chain of an amino acid;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein each of R4aand R4b, when present, is independently selected from hydrogen and C1-C4 alkyl;wherein R6is a side chain of an amino acid;wherein R10is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3,wherein R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine; andwherein each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid.

[0457] 99. The method of embodiment 98, wherein each of m and n is 0.

[0458] 100. The method of embodiment 98, wherein m is 1.

[0459] 101. The method of any one of embodiments 98-100, wherein 0 is 0.

[0460] 102. The method of any one of embodiments 98-100, wherein 0 is 1.

[0461] 103. The method of any one of embodiments 98-102, wherein p is an integer from 0 to 25.

[0462] 104. The method of any one of embodiments 98-103, wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0463] 105. The method of any one of embodiments 98-104, wherein p is selected from 0 and 1.

[0464] 106. The method of any one of embodiments 98-105, wherein r is 0.

[0465] 107. The method of any one of embodiments 98-106, wherein s is 1.

[0466] 108. The method of any one of embodiments 98-107, wherein each of r and v is 0.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0467] 109. The method of any one of embodiments 98-107, wherein v is 1.

[0468] 110. The method of any one of embodiments 98-109, wherein w is 0.

[0469] 111. The method of any one of embodiments 98-109, wherein w is 1.

[0470] 112. The method of any one of embodiments 98-111, wherein A is S.

[0471] 113. The method of any one of embodiments 98-112, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2).

[0472] 114. The method of any one of embodiments 98-113, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).

[0473] 115. The method of any one of embodiments 98-114, wherein Q2is *-CO2-(C4-C8 alkylene)-OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

[0474] 116. The method of any one of embodiments 98-115, wherein Q2is *-CO2CH2CH=CHCH2OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

[0475] 117. The method of any one of embodiments 98-116, wherein Q2is a chemically cleavable moiety.

[0476] 118. The method of embodiment 117, wherein the chemically cleavable moiety is a protease recognition sequence.

[0477] 119. The method of embodiment 118, wherein the protease recognition sequence is a TEV recognition sequence.

[0478] 120. The method of embodiment 119, wherein the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).

[0479] 121. The method of any one of embodiments 98-120, wherein each of R1', R1’, and R1", when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, -(C1-C4)C(O)NH2, and -(C1-C4)Ar1.

[0480] 122. The method of any one of embodiments 98-120, wherein at least one of R1', R1’, and R1", when present, is not hydrogen.

[0481] 123. The method of any one of embodiments 98-121, wherein each of R1', R1’, and R1", when present, is hydrogen.

[0482] 124. The method of any one of embodiments 98-123, wherein R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0483] 125. The method of any one of embodiments 98-123, wherein each of R3, R7, and R11is not a glycine side chain.

[0484] 126. The method of any one of embodiments 98-123, wherein each of R3, R7, and R11is a glycine side chain.

[0485] 127. The any one of embodiments 98-126, wherein each of R4aand R4bis hydrogen.

[0486] 128. The method of any one of embodiments 98-127, wherein R6is hydrogen.

[0487] 129. The method of any one of embodiments 98-128, wherein R7is a side chain of an amino acid selected from glycine and alanine.

[0488] 130. The method of any one of embodiments 98-129, wherein R7is an alanine side chain.

[0489] 131. The method of any one of embodiments 98-130, wherein R10is -CO2H or a structure:[chemical structure image - OCR garbled rendering of tetrazole structure]

[0490] 132. The method of any one of embodiments 98-131, wherein R10is -CO2H.

[0491] 133. The method of any one of embodiments 98-132, wherein R11is a side chain of an amino acid selected from glycine and alanine.

[0492] 134. The method of any one of embodiments 98-133, wherein R11is an alanine side chain.

[0493] 135. The method of any one of embodiments 98-132, wherein R11is not a glycine side chain.

[0494] 136. The method of any one of embodiments 98-135, wherein R12is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0495] 137. The method of any one of embodiments 98-136, wherein R12is a side chain of an amino acid selected from alanine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, and glycine.

[0496] 138. The method of any one of embodiments 98-137, wherein R12is a glycine side chain.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0497] 139. The method of any one of embodiments 98-138, wherein each of R13aand R13bis independently selected -CCH, -CH2N3, and a side chain of an amino acid.

[0498] 140. The method of any one of embodiments 98-139, wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.

[0499] 141. The method of any one of embodiments 98-140, wherein Ar1is an unsubstituted 6-membered aryl.

[0500] 142. The method of any one of embodiments 98-141, wherein the compound comprises one or more D-amino acid residues.

[0501] 143. The method of any one of embodiments 98-142, wherein the compound comprises one or more p-amino acid residues.

[0502] 144. The method of any one of embodiments 98-143, wherein the compound comprises one or more N-methylated amino acid residues.

[0503] 145. The method of any one of embodiments 98-144, wherein PapB installs a single thioether linkage in the compound.

[0504] 146. The method of any one of embodiments 98-145, wherein PapB installs two or more thioether linkages in the compound.

[0505] 147. The method of any one of embodiments 98-146, wherein the compound has a structure represented by a formula:

[0506] 148. The method of any one of embodiments 98-147, wherein the compound has a structure represented by a formula:

[0507] 149. The method of any one of embodiments 98-148, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0508] 150. The method of any one of embodiments 98-149, wherein the compound has a structure represented by a formula:

[0509] 151. The method of any one of embodiments 72-98-150, wherein the compound has a structure represented by a formula:

[0510] 152. The method of any one of embodiments 98-147, wherein the compound has a structure represented by a formula:

[0511] 153. The method of any one of embodiments 98-147, wherein the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0512] 154. The method of any one of embodiments 98-147 and 153, wherein the thioether or selenoether compound has a structure represented by a formula:

[0513] 155. The method of any one of embodiments 98-147 and 153, wherein the thioether compound has a structure represented by a formula:

[0514] 156. The method of any one of embodiments 98-147 and 153, wherein the thioether or selenoether compound has a structure represented by a formula:

[0515] 157. The method of any one of embodiments 98-147, 153, and 157, wherein the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0516] 158. The method of any one of embodiments 98-158, wherein the method further comprises adding a reducing agent.

[0517] 159. The method of embodiment 158, wherein the reducing agent comprises dithionite, flavodoxin, flavodoxin reductase, titanium citrate, reduced nicotinamide adenine dinucleotide phosphate, or any combination thereof.

[0518] 160. The method of any one of embodiments 98-159, wherein the method further comprises adding a protease.

[0519] 161. The method of embodiment 160, wherein the protease is selected from a TEV protease, chymotrypsin, and trypsin.

[0520] 162. The method of any one of embodiments 98-161, wherein the method produces a thioether or selenoether compound having a structure represented by a formula:

[0521] 163. The method of any one of embodiments 98-162, wherein the thioether or selenoether compound has a structure represented by a formula:

[0522] 164. The method of any one of embodiments 98-161, wherein the thioether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0523] 165. The method of any one of embodiments 98-161 and 164, wherein the thioether compound has a structure represented by a formula:

[0524] 166. A thioether or selenoether compound produced by the method of any one of embodiments 98-165.

[0525] 167. A thioether or selenoether compound having a structure represented by the formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein v is selected from 0, 1, 2, 3, and 4;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein Z is *-NH(CH2CH2O)uCH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein u is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1andSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1', or R1' is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3and R7is independently a side chain of an amino acid; wherein each of R4aand R4bis independently selected from hydrogen and C1-C4 alkyl;wherein R5is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:wherein each of R6and R8is independently a side chain of an amino acid; andwherein R9is selected from -C(O)OH, -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2.

[0526] 168. The thioether or selenoether compound of embodiment 167, wherein each of m and n is 0.

[0527] 169. The thioether or selenoether compound of embodiment 167, wherein m is 1.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0528] 170. The thioether or selenoether compound of any one of embodiments 167-169, wherein o is 0.

[0529] 171. The thioether or selenoether compound of any one of embodiments 167-169, wherein o is 1.

[0530] 172. The thioether or selenoether compound of any one of embodiments 167-171, wherein p is an integer from 0 to 25.

[0531] 173. The thioether or selenoether compound of any one of embodiments 167-172, wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0532] 174. The thioether or selenoether compound of any one of embodiments 167-173, wherein p is selected from 0 and 1.

[0533] 175. The thioether or selenoether compound of any one of embodiments 167-174, wherein r is 0.

[0534] 176. The thioether or selenoether compound of any one of embodiments 167-175, wherein s is 1.

[0535] 177. The thioether or selenoether compound of any one of embodiments 167-176, wherein A is S.

[0536] 178. The thioether or selenoether compound of any one of embodiments 167-177, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2).

[0537] 179. The thioether or selenoether compound of any one of embodiments 167-178, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).

[0538] 180. The thioether or selenoether compound of any one of embodiments 167-179, wherein Q2is *-CO2-(C4-C8 alkylene)-OC(O)-**, wherein denotes a bond connected to Q1and ** denotes a bond connected to Z.

[0539] 181. The thioether or selenoether compound of any one of embodiments 167-180, wherein Q2is *-CO2CH2CH=CHCH2OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

[0540] 182. The thioether or selenoether compound of any one of embodiments 167-181, wherein Q2is a chemically cleavable moiety.

[0541] 183. The thioether or selenoether compound of embodiment 182, wherein the chemically cleavable moiety is a protease recognition sequence.

[0542] 184. The thioether or selenoether compound of embodiment 183, wherein the protease recognition sequence is a TEV recognition sequence.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0543] 185. The thioether or selenoether compound of embodiment 184, wherein the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).

[0544] 186. The thioether or selenoether compound of any one of embodiments 167-185, wherein each of R1', R1’, and R1", when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, -(C1-C4)C(O)NH2, and -(C1-C4)Ar1.

[0545] 187. The thioether or selenoether compound of any one of embodiments 167-186, wherein at least one of R1', R1’, and R1", when present, is not hydrogen.

[0546] 188. The thioether or selenoether compound of any one of embodiments 167-186, wherein each of R1', R1’, and R1", when present, is hydrogen.

[0547] 189. The thioether or selenoether compound of any one of embodiments 167-188, wherein each of R2, R2’, and R2", when present, is independently a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0548] 190. The thioether or selenoether compound of any one of embodiments 167-189, wherein R3is a side chain of an amino acid selected from glycine, alanine, cysteine, homocysteine, and selenocysteine.

[0549] 191. The thioether or selenoether compound of any one of embodiments 167-190, wherein R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.

[0550] 192. The thioether or selenoether compound of any one of embodiments 167-191, wherein each of R3and R7is not hydrogen.

[0551] 193. The thioether or selenoether compound of any one of embodiments 167-192, wherein each of R4aand R4bis hydrogen.

[0552] 194. The thioether or selenoether compound of any one of embodiments 167-193, wherein R5is -CO2H or a structure:HN 'N=N

[0553] 195. The thioether or selenoether compound of any one of embodiments 167-194, wherein R5is -CO2H.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0554] 196. The thioether or selenoether compound of any one of embodiments 167-195, wherein R6is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0555] 197. The thioether or selenoether compound of any one of embodiments 167-196, wherein R6is a glycine side chain.

[0556] 198. The thioether or selenoether compound of any one of embodiments 167-197, wherein R7is a side chain of an amino acid selected from glycine and alanine.

[0557] 199. The thioether or selenoether compound of any one of embodiments 167-198, wherein R7is an alanine side chain.

[0558] 200. The thioether or selenoether compound of any one of embodiments 167-199, wherein R8is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, phenylalanine, tyrosine, and tryptophan.

[0559] 201. The thioether or selenoether compound of any one of embodiments 167-200, wherein R8is an alanine side chain.

[0560] 202. The thioether or selenoether compound of any one of embodiments 167-201, wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.

[0561] 203. The thioether or selenoether compound of any one of embodiments 167-202, wherein Ar1is an unsubstituted 6-membered aryl.

[0562] 204. The thioether or selenoether compound of any one of embodiments 167-203, having a structure represented by the formula:

[0563] 205. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0564] 206. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by a formula selected from:

[0565] 207. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0566] 208. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0567] 209. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0568] 210. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0569] 211. The thioether or selenoether compound of any one of embodiments 167-203, having a structure represented by the formula:

[0570] 212. The thioether or selenoether compound of any one of embodiments 167-211, having the amino acid sequence GC1XANZ1A (SEQ ID NO: 9), wherein X is any amino acid, Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1.

[0571] 213. The thioether or selenoether compound of any one of embodiments 167-212, having the amino acid sequence GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

[0572] 214. The thioether or selenoether compound of any one of embodiments 167-211, having the amino acid sequence YGC1XANZ1A (SEQ ID NO: 12), wherein X is any amino acid, Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1.

[0573] 215. The thioether or selenoether compound of any one of embodiments 167-212, having the amino acid sequence YGC1XANZ1A (SEQ ID NO:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 13), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

[0574] 216. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0575]

[0576] 217. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0577] 218. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by a formula selected from:

[0578] 219. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0579] 220. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0580] 221. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0581] 222. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by a formula selected from:

[0582] 223. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0583] 224. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0584] 225. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0585] 226. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0586] 227. The thioether or selenoether compound of any one of embodiments 167-204, having a structure represented by the formula:

[0587] 228. A thioether or selenoether compound having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v’, and a structure selected from:wherein V is selected from 1, 2, 3, and 4;wherein Z is *-NH(CH2CH2O)w'CH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein w’ is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1 -C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3, R7, and R11is independently a side chain of an amino acid;wherein each of R4aand R4b, when present, is independently selected from hydrogen and C1-C4 alkyl;wherein R6is a side chain of an amino acid;wherein R10is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, ucture selected from:wherein R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine; andwherein each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid.

[0588] 229. The thioether or selenoether compound of embodiment 228, wherein each of m and n is 0.

[0589] 230. The thioether or selenoether compound of embodiment 228, wherein m is 1.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0590] 231. The thioether or selenoether compound of any one of embodiments 228-230, wherein o is 0.

[0591] 232. The thioether or selenoether compound of any one of embodiments 228-230, wherein o is 1.

[0592] 233. The thioether or selenoether compound of any one of embodiments 228-232, wherein p is an integer from 0 to 25.

[0593] 234. The thioether or selenoether compound of any one of embodiments 228-233, wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

[0594] 235. The thioether or selenoether compound of any one of embodiments 228-234, wherein p is selected from 0 and 1.

[0595] 236. The thioether or selenoether compound of any one of embodiments 228-235, wherein r is 0.

[0596] 237. The thioether or selenoether compound of any one of embodiments 228-236, wherein s is 1.

[0597] 238. The thioether or selenoether compound of any one of embodiments 228-237, wherein each of and v is 0.

[0598] 239. The thioether or selenoether compound of any one of embodiments 228-238, wherein v is 1.

[0599] 240. The thioether or selenoether compound of any one of embodiments 228-239, wherein w is 0.

[0600] 241. The thioether or selenoether compound of any one of embodiments 228-239, wherein w is 1.

[0601] 242. The thioether or selenoether compound of any one of embodiments 228-241, wherein A is S.

[0602] 243. The thioether or selenoether compound of any one of embodiments 228-242, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2).

[0603] 244. The thioether or selenoether compound of any one of embodiments 228-243, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).

[0604] 245. The thioether or selenoether compound of any one of embodiments 228-244, wherein Q2is *-CO2-(C4-C8 alkylene)-OC(O)-**, wherein denotes a bond connected to Q1and ** denotes a bond connected to Z.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0605] 246. The thioether or selenoether compound of any one of embodiments 228-245, wherein Q2is *-CO2CH2CH=CHCH2OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

[0606] 247. The thioether or selenoether compound of any one of embodiments 228-246, wherein Q2is a chemically cleavable moiety.

[0607] 248. The thioether or selenoether compound of embodiment 247, wherein the chemically cleavable moiety is a protease recognition sequence.

[0608] 249. The thioether or selenoether compound of embodiment 248, wherein the protease recognition sequence is a TEV recognition sequence.

[0609] 250. The thioether or selenoether compound of embodiment 249, wherein the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).

[0610] 251. The thioether or selenoether compound of any one of embodiments 228-250, wherein each of R1', R1’, and R1", when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, -(C1-C4)C(O)NH2, and -(C1-C4)Ar1.

[0611] 252. The thioether or selenoether compound of any one of embodiments 228-251, wherein at least one of R1', R1’, and R1", when present, is not hydrogen.

[0612] 253. The thioether or selenoether compound of any one of embodiments 228-252, wherein each of R1', R1’, and R1", when present, is hydrogen.

[0613] 254. The thioether or selenoether compound of any one of embodiments 228-253, wherein R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.

[0614] 255. The thioether or selenoether compound of any one of embodiments 228-254, wherein each of R3, R7, and R11is not a glycine side chain.

[0615] 256. The thioether or selenoether compound of any one of embodiments 228-255, wherein each of R3, R7, and R11is a glycine side chain.

[0616] 257. The any one of embodiments 228-256, wherein each of R4aand R4bis hydrogen.

[0617] 258. The thioether or selenoether compound of any one of embodiments 228-257, wherein R6is hydrogen.

[0618] 259. The thioether or selenoether compound of any one of embodiments 228-258, wherein R7is a side chain of an amino acid selected from glycine and alanine.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0619] 260. The thioether or selenoether compound of any one of embodiments 228-259, wherein R7is an alanine side chain.

[0620] 261. The thioether or selenoether compound of any one of embodiments 228-260, wherein R10is -CO2H or a structure:, N.HN 7 'N=N

[0621] 262. The thioether or selenoether compound of any one of embodiments 228-261, wherein R10is-CC^H.

[0622] 263. The thioether or selenoether compound of any one of embodiments 228-262, wherein R11is a side chain of an amino acid selected from glycine and alanine.

[0623] 264. The thioether or selenoether compound of any one of embodiments 228-263, wherein R11is an alanine side chain.

[0624] 265. The thioether or selenoether compound of any one of embodiments 228-262, wherein R11is not a glycine side chain.

[0625] 266. The thioether or selenoether compound of any one of embodiments 228-265, wherein R12is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

[0626] 267. The thioether or selenoether compound of any one of embodiments 228-266, wherein R12is a side chain of an amino acid selected from alanine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, and glycine.

[0627] 268. The thioether or selenoether compound of any one of embodiments 228-267, wherein R12is a glycine side chain.

[0628] 269. The thioether or selenoether compound of any one of embodiments 228-268, wherein each of R13aand R13bis independently selected -CCH, -CH2N3, and a side chain of an amino acid.

[0629] 270. The thioether or selenoether compound of any one of embodiments 228-269, wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.

[0630] 271. The thioether or selenoether compound of any one of embodiments 228-270, wherein Ar1is an unsubstituted 6-membered aryl.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0631] 272. The thioether or selenoether compound of any one of embodiments 228-271, wherein the compound comprises one or more D-amino acid residues.

[0632] 273. The thioether or selenoether compound of any one of embodiments 228-272, wherein the compound comprises one or more p-amino acid residues.

[0633] 274. The thioether or selenoether compound of any one of embodiments 228-272, wherein the compound comprises one or more N-methylated amino acid residues.

[0634] 275. The thioether or selenoether compound of any one of embodiments 228-274, having a structure represented by the formula:

[0635] 276. The thioether or selenoether compound of any one of embodiments 228-275, having a structure represented by the formula:

[0636] 277. The thioether or selenoether compound of any one of embodiments 228-275, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0637] 278. The thioether or selenoether compound of any one of embodiments 228-275, having a structure represented by the formula:

[0638]

[0639] 279. The thioether or selenoether compound of any one of embodiments 228-275, having a structure represented by the formula:

[0640] 280. The thioether or selenoether compound of any one of embodiments 228-275, having a structure represented by the formula:

[0641] 281. The thioether or selenoether compound of any one of embodiments 228-275, having a structure represented by the formula:

[0642] 282. The thioether or selenoether compound of any one of embodiments 228-275, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1

[0643] 283. The thioether or selenoether compound of any one of embodiments 228-275, having a structure represented by the formula:

[0644] It will be apparent to those skilled in the art that various modifications and variations can be made in the present technology without departing from the scope or spirit of the technology. Other embodiments of the technology will be apparent to those skilled in the art from consideration of the specification and practice of the technology disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the technology being indicated by the following claims.

Claims

SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1CLAIMSI / We claim:

1. A method of chemically modifying a compound to install a thioether or a selenoether linkage, the method comprising reacting the compound with PapB, wherein the compound has a structure represented by a formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein t is selected from 1, 2, 3, 4, and 5;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein Z is *-NH(CH2CH2O)uCH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein u is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1andSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, 01 -C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3and R7is independently a side chain of an amino acid; wherein each of R4aand R4bis independently selected from hydrogen and C1-C4 alkyl;wherein R5is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:wherein each of R6and R8is independently a side chain of an amino acid; and wherein R9is selected from -C(O)OH, -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2.

2. The method of claim 1, wherein each of m and n is 0.

3. The method of claim 1, wherein m is 1.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 4. The method of any one of claims 1-3, wherein o is 0.

5. The method of any one of claims 1-3, wherein o is 1.

6. The method of any one of claims 1-5, wherein p is an integer from 0 to 25.

7. The method of any one of claims 1 -6, wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

8. The method of any one of claims 1-7, wherein p is selected from 0 and 1.

9. The method of any one of claims 1-8, wherein r is 0.

10. The method of any one of claims 1 -9, wherein s is 1.

11. The method of any one of claims 1-10, wherein A is S.

12. The method of any one of claims 1-11, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2).

13. The method of any one of claims 1-12, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).

14. The method of any one of claims 1-13, wherein Q2is *-CO2-(C4-C8 alkylene)-OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

15. The method of any one of claims 1-14, wherein Q2is*-CO2CH2CH=CHCH2OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

16. The method of any one of claims 1-15, wherein Q2 is a chemically cleavable moiety.

17. The method of claim 16, wherein the chemically cleavable moiety is a protease recognition sequence.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 18. The method of claim 17, wherein the protease recognition sequence is a TEV recognition sequence.

19. The method of claim 18, wherein the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).

20. The method of any one of claims 1-19, wherein each of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, -(C1-C4)C(O)NH2, and -(C1-C4)Ar1.

21. The method of any one of claims 1-19, wherein at least one of R1, R1”, and R1”, when present, is not hydrogen.

22. The method of any one of claims 1-20, wherein each of R1, R1’, and R1”, when present, is hydrogen.

23. The method of any one of claims 1-22, wherein each of R2, R2’, and R2”, when present, is independently a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

24. The method of any one of claims 1-23, wherein R3is a side chain of an amino acid selected from glycine, alanine, cysteine, homocysteine, and selenocysteine.

25. The method of any one of claims 1-24, wherein R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.

26. The method of any one of claims 1-25, wherein each of R3and R7is not hydrogen.

27. The method of any one of claims 1-26, wherein each of R4aand R4bis hydrogen.

28. The method of any one of claims 1-27, wherein R5is -CO2H or a structure:L HN 7vN=N29. The method of any one of claims 1-27, wherein R5is -CO2H.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 30. The method of any one of claims 1-29, wherein R6is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

31. The method of any one of claims 1-30, wherein R6is a glycine side chain.

32. The method of any one of claims 1-31, wherein R7is a side chain of an amino acid selected from glycine and alanine.

33. The method of any one of claims 1-32, wherein R7is an alanine side chain.

34. The method of any one of claims 1-33, wherein R8is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, phenylalanine, tyrosine, and tryptophan.

35. The method of any one of claims 1-34, wherein R8is an alanine side chain.

36. The method of any one of claims 1-35, wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.

37. The method of any one of claims 1-36, wherein Ar1is an unsubstituted 6-membered aryl.

38. The method of any one of claims 1-37, wherein the compound comprises one or more D-amino acid residues.

39. The method of any one of claims 1-38, wherein the compound comprises one or more p-amino acid residues.

40. The method of any one of claims 1-39, wherein the compound comprises one or more N-methylated amino acid residues.

41. The method of any one of claims 1-40, wherein PapB installs a single thioether linkage in the compound.

42. The method of any one of claims 1-40, wherein PapB installs two or more thioether linkages in the compound.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 43. The method of any one of claims 1-42, wherein the compound has a structure44. The method of any one of claims 1-43, wherein the compound has a structure represented by a formula:

45. The method of any one of claims 1-43, wherein the compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P146. The method of any one of claims 1-43, wherein the compound has a structure represented by a formula:

47. The method of any one of claims 1-43, wherein the compound has a structure represented by a formula:

48. The method of any one of claims 1-44 and 47, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 49. The method of any one of claims 1-43, 46, and 47, wherein the compound has a structure represented by a formula:

50. The method of any one of claims 1-44, 46, and 47, wherein the compound has a structure represented by a formula:

51. The method of any one of claims 1-44 and 46-50, wherein the compound comprises an amino acid sequence GCXANZA (SEQ ID NO: 7), wherein X is any amino acid and Z is a peptoid-based amino acid capable of forming a intrapeptide thioether linkage.

52. The method of any one of claims 1-44 and 46-50, wherein the compound comprises an amino acid sequence YGCXANZA (SEQ ID NO: 10), wherein X is any amino acid and Z is a peptoid-based amino acid capable of forming a intrapeptide thioether linkage.

53. The method of claim 51 or 52, wherein X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate.

54. The method of any one of claims 51 and 53, wherein X is sarcosine and Z is from N-glutamate.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 55. The method of any one of claims 1-44, 46-51, 53, and 54, wherein the compound comprises an amino acid sequence GCXANZA (SEQ ID NO: 8), wherein X is sarcosine and Z is N-glutamate.

56. The method of any one of claims 1-44, 46-50, and 52-54, wherein the compound comprises an amino acid sequence YGCXANZA (SEQ ID NO: 11), wherein X is sarcosine and Z is N-glutamate.

57. The method of any one of claims 1-42, wherein the compound has a structure represented by a formula:

58. The method of any one of claims 1-42 and 57, wherein the compound has a structure represented by a formula:

59. The method of any one of claims 1-42 and 57, wherein the compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P160. The method of any one of claims 1-42 and 57, wherein the compound has a structure represented by a formula:

61. The method of any one of claims 1-42 and 57, wherein the compound has a structure represented by a formula:

62. The method of any one of claims 1-42, 57, and 61, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 63. The method of any one of claims 1-42, 57, 61, and 62, wherein the compound has a structure represented by a formula selected from:

64. The method of any one of claims 1-42, 57, and 61, wherein the compound has a structure represented by a formula:

65. The method of any one of claims 1-42 and 57, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 66. The method of any one of claims 1-42, 57, and 65, wherein the compound has a structure represented by a formula:

67. The method of any one of claims 1-42, wherein the thioether or selenoether compound has a structure represented by a formula:wherein v is t-1.

68. The method of any one of claims 1-43 and 67, wherein the thioether or selenoether compound has a structure represented by a formula:

69. The method of any one of claims 1-44, 67, and 68, wherein the thioether or selenoether compound has a structure represented by a formula:

70. The method of any one of claims 1-43, 45, 67, and 68, wherein the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P171. The method of any one of claims 1-43 and 67, wherein the thioether or selenoether compound has a structure represented by a formula:

72. The method of any one of claims 1-43 and 67, wherein the thioether or selenoether compound has a structure represented by a formula:

73. The method of any one of claims 1-44, 47, 67, and 72, wherein the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 74. The method of any one of claims 1-43, 46, 47, 67, and 72, wherein the thioether or selenoether compound has a structure represented by a formula:

75. The method of any one of claims 1-44, 46, 47, 67, and 72, wherein the thioether or selenoether compound has a structure represented by a formula:

76. The method of any one of claims 1-44, 46-50, 67-69, and 71-75, wherein the thioether or selenoether compound has an amino acid sequence GC1XANZ1A (SEQ ID NO: 9), wherein X is any amino acid, Z is a peptoid-based amino acid capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1.

77. The method of any one of claims 1-44, 46-50, 67-69, and 71-75, wherein the thioether or selenoether compound has an amino acid sequence YGC1XANZ1A (SEQ ID NO: 12), wherein X is any amino acid, Z is a peptoid-based amino acid capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1.

78. The method of any one of claims 1-44, 46-50, 67-69, and 71-77, wherein X is a peptoid-based amino acid and Z is selected from N-glutamate, N-aspartate, and N-homoglutamate.

79. The method of any one of claims 1-44, 46-50, 67-69, and 71-78, wherein X is sarcosine and Z is N-glutamate.

80. The method of any one of claims 1-44, 46-51, 53-55, 67-69, 71-76, 78, and 79, wherein the thioether or selenoether compound has an amino acid sequenceSMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

81. The method of any one of claims 1-44, 46-50, 52-54, 56, 67-69, 71-75, and 77-79, wherein the thioether or selenoether compound has an amino acid sequence YGC1XANZ1A (SEQ ID NO: 13), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

82. The method of any one of claims 1-42 and 57, wherein the thioether or selenoether compound has a structure represented by a formula:

83. The method of any one of claims 1-42, 57, 58, and 82, wherein the thioether or selenoether compound has a structure represented by a formula:

84. The method of any one of claims 1-42, 57, 59, and 82, wherein the thioether or selenoether compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P185. The method of any one of claims 1-42, 57, 60, and 82, wherein the thioether compound has a structure represented by a formula:

86. The method of any one of claims 1-42, 57, 61, and 82, wherein the thioether or selenoether compound has a structure represented by a formula:

87. The method of any one of claims 1-42, 57, 62, 82, and 86, wherein the thioether or selenoether compound has a structure represented by a formula:

88. The method of any one of claims 1-42, 57, 62, 82, and 86, wherein the thioether compound has a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P189. The method of any one of claims 1-42, 57, and 82, wherein the thioether compound has a structure represented by a formula:

90. The method of any one of claims 1-89, wherein the method further comprises adding a reducing agent.

91. The method of claim 90, wherein the reducing agent comprises dithionite, flavodoxin, flavodoxin reductase, titanium citrate, reduced nicotinamide adenine dinucleotide phosphate, or any combination thereof.

92. The method of any one of claims 1-91, wherein the method further comprises adding a protease.

93. The method of any one of claims 1-92, wherein the method produces a thioether or selenoether compound having a structure represented by a formula:wherein v is t-1.

94. The method of any one of claims 1-93, wherein the thioether or selenoether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P195. The method of any one of claims 1-94, wherein the thioether compound has a structure represented by a formula:

96. The method of any one of claims 1-94, wherein the thioether or selenoether compound has a structure represented by a formula:

97. A thioether or selenoether compound produced by the method of any one of claims 1-96.

98. A method of chemically modifying a compound to install a thioether or a selenoether linkage, the method comprising reacting the compound with PapB, wherein the compound has a structure represented by a formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v', and a structure selected from:wherein v’ is selected from 1, 2, 3, and 4;wherein Z is *-NH(CH2CH2O)wCH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein w’ is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1 -C4 alkyl, 01-04 hydroxyalkyl, 01 -C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1selected from a 5- to 10-membered heteroaryl and a 6- to 10-SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, 01-04 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3, R7, and R11is independently a side chain of an amino acid; wherein each of R4aand R4b, when present, is independently selected from hydrogen and C1-C4 alkyl;wherein R6is a side chain of an amino acid;wherein R10is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, structure selected from:wherein R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine; andwherein each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid.

99. The method of claim 98, wherein each of m and n is 0.

100. The method of claim 98, wherein m is 1.

101. The method of any one of claims 98-100, wherein 0 is 0.

102. The method of any one of claims 98-100, wherein 0 is 1.

103. The method of any one of claims 98-102, wherein p is an integer from 0 to 25.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 104. The method of any one of claims 98-103, wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

105. The method of any one of claims 98-104, wherein p is selected from 0 and 1.

106. The method of any one of claims 98-105, wherein r is 0.

107. The method of any one of claims 98-106, wherein s is 1.

108. The method of any one of claims 98-107, wherein each of r and v is 0.

109. The method of any one of claims 98-107, wherein v is 1.

110. The method of any one of claims 98-109, wherein w is 0.

111. The method of any one of claims 98-109, wherein w is 1.

112. The method of any one of claims 98-111, wherein A is S.

113. The method of any one of claims 98-112, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2).

114. The method of any one of claims 98-113, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).

115. The method of any one of claims 98-114, wherein Q2is *-CO2-(C4-C8 alkylene)-OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

116. The method of any one of claims 98-115, wherein Q2is*-CO2CH2CH=CHCH2OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

117. The method of any one of claims 98-116, wherein Q2is a chemically cleavable moiety.

118. The method of claim 117, wherein the chemically cleavable moiety is a protease recognition sequence.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 119. The method of claim 118, wherein the protease recognition sequence is a TEV recognition sequence.

120. The method of claim 119, wherein the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).

121. The method of any one of claims 98-120, wherein each of R1', R1', and R1", when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, -(C1-C4)C(O)NH2, and -(C1-C4)Ar1.

122. The method of any one of claims 98-120, wherein at least one of R1', R1', and R1", when present, is not hydrogen.

123. The method of any one of claims 98-121, wherein each of R1', R1’, and R1", when present, is hydrogen.

124. The method of any one of claims 98-123, wherein R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.

125. The method of any one of claims 98-123, wherein each of R3, R7, and R11is not a glycine side chain.

126. The method of any one of claims 98-123, wherein each of R3, R7, and R11is a glycine side chain.

127. The any one of claims 98-126, wherein each of R4aand R4bis hydrogen.

128. The method of any one of claims 98-127, wherein R6is hydrogen.

129. The method of any one of claims 98-128, wherein R7is a side chain of an amino acid selected from glycine and alanine.

130. The method of any one of claims 98-129, wherein R7is an alanine side chain.

131. The method of any one of claims 98-130, wherein R10is -CO2H or a structure:

132. The method of any one of claims 98-131, wherein R10is -CO2H.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 133. The method of any one of claims 98-132, wherein R11is a side chain of an amino acid selected from glycine and alanine.

134. The method of any one of claims 98-133, wherein R11is an alanine side chain.

135. The method of any one of claims 98-132, wherein R11is not a glycine side chain.

136. The method of any one of claims 98-135, wherein R12is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

137. The method of any one of claims 98-136, wherein R12is a side chain of an amino acid selected from alanine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, and glycine.

138. The method of any one of claims 98-137, wherein R12is a glycine side chain.

139. The method of any one of claims 98-138, wherein each of R13aand R13bis independently selected -CCH, -CH2N3, and a side chain of an amino acid.

140. The method of any one of claims 98-139, wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.

141. The method of any one of claims 98-140, wherein Ar1is an unsubstituted 6-membered aryl.

142. The method of any one of claims 98-141, wherein the compound comprises one or more D-amino acid residues.

143. The method of any one of claims 98-142, wherein the compound comprises one or more p-amino acid residues.

144. The method of any one of claims 98-143, wherein the compound comprises one or more N-methylated amino acid residues.

145. The method of any one of claims 98-144, wherein PapB installs a single thioether linkage in the compound.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 146. The method of any one of claims 98-145, wherein PapB installs two or more thioether linkages in the compound.

147. The method of any one of claims 98-146, wherein the compound has a structure represented by a formula:

148. The method of any one of claims 98-147, wherein the compound has a structure represented by a formula:

149. The method of any one of claims 98-148, wherein the compound has a structure represented by a formula:

150. The method of any one of claims 98-149, wherein the compound has a structure represented by a formula:

151. The method of any one of claims 72-98-150, wherein the compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1152. The method of any one of claims 98-147, wherein the compound has a structure represented by a formula:

153. The method of any one of claims 98-147, wherein the thioether or selenoether compound has a structure represented by a formula:

154. The method of any one of claims 98-147 and 153, wherein the thioether or selenoether compound has a structure represented by a formula:

155. The method of any one of claims 98-147 and 153, wherein the thioether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1156. The method of any one of claims 98-147 and 153, wherein the thioether or selenoether compound has a structure represented by a formula:

157. The method of any one of claims 98-147, 153, and 157, wherein the thioether or selenoether compound has a structure represented by a formula:

158. The method of any one of claims 98-158, wherein the method further comprises adding a reducing agent.

159. The method of claim 158, wherein the reducing agent comprises dithionite, flavodoxin, flavodoxin reductase, titanium citrate, reduced nicotinamide adenine dinucleotide phosphate, or any combination thereof.

160. The method of any one of claims 98-159, wherein the method further comprises adding a protease.

161. The method of claim 160, wherein the protease is selected from a TEV protease, chymotrypsin, and trypsin.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 162. The method of any one of claims 98-161, wherein the method produces a thioether or selenoether compound having a structure represented by a formula:

163. The method of any one of claims 98-162, wherein the thioether or selenoether compound has a structure represented by a formula:

164. The method of any one of claims 98-161, wherein the thioether compound has a structure represented by a formula:

165. The method of any one of claims 98-161 and 164, wherein the thioether compound has a structure represented by a formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 166. A thioether or selenoether compound produced by the method of any one of claims 98-165.

167. A thioether or selenoether compound having a structure represented by the formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;wherein s is selected from 1 and 2;wherein v is selected from 0, 1, 2, 3, and 4;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein Z is *-NH(CH2CH2O)uCH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein u is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively,SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;wherein each of R3and R7is independently a side chain of an amino acid; wherein each of R4aand R4bis independently selected from hydrogen and C1-C4 alkyl;wherein R5is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, -P(O)(OH)2, and a structure selected from:wherein each of R6and R8is independently a side chain of an amino acid; and wherein R9is selected from -C(O)OH, -CH2OH, -CH2SH, -CH2NH2, and -C(O)NH2.

168. The thioether or selenoether compound of claim 167, wherein each of m and n is 0.

169. The thioether or selenoether compound of claim 167, wherein m is 1.

170. The thioether or selenoether compound of any one of claims 167-169, wherein o is 0.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 171. The thioether or selenoether compound of any one of claims 167-169, wherein o is 1.

172. The thioether or selenoether compound of any one of claims 167-171, wherein p is an integer from 0 to 25.

173. The thioether or selenoether compound of any one of claims 167-172, wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

174. The thioether or selenoether compound of any one of claims 167-173, wherein p is selected from 0 and 1.

175. The thioether or selenoether compound of any one of claims 167-174, wherein r is 0.

176. The thioether or selenoether compound of any one of claims 167-175, wherein s is 1.

177. The thioether or selenoether compound of any one of claims 167-176, wherein A is S.

178. The thioether or selenoether compound of any one of claims 167-177, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2).

179. The thioether or selenoether compound of any one of claims 167-178, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).

180. The thioether or selenoether compound of any one of claims 167-179, wherein Q2is *-CO2-(C4-C8 alkylene)-OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

181. The thioether or selenoether compound of any one of claims 167-180, wherein Q2is *-CO2CH2CH=CHCH2OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

182. The thioether or selenoether compound of any one of claims 167-181, wherein Q2is a chemically cleavable moiety.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 183. The thioether or selenoether compound of claim 182, wherein the chemically cleavable moiety is a protease recognition sequence.

184. The thioether or selenoether compound of claim 183, wherein the protease recognition sequence is a TEV recognition sequence.

185. The thioether or selenoether compound of claim 184, wherein the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).

186. The thioether or selenoether compound of any one of claims 167-185, wherein each of R1, R1’, and R1", when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 aminoalkyl, -(C1-C4)C(O)NH2, and -(C1-C4)Ar1.

187. The thioether or selenoether compound of any one of claims 167-186, wherein at least one of R1', R1', and R1", when present, is not hydrogen.

188. The thioether or selenoether compound of any one of claims 167-186, wherein each of R1', R1’, and R1", when present, is hydrogen.

189. The thioether or selenoether compound of any one of claims 167-188, wherein each of R2, R2’, and R2", when present, is independently a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

190. The thioether or selenoether compound of any one of claims 167-189, wherein R3is a side chain of an amino acid selected from glycine, alanine, cysteine, homocysteine, and selenocysteine.

191. The thioether or selenoether compound of any one of claims 167-190, wherein R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.

192. The thioether or selenoether compound of any one of claims 167-191, wherein each of R3and R7is not hydrogen.

193. The thioether or selenoether compound of any one of claims 167-192, wherein each of R4aand R4bis hydrogen.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 194. The thioether or selenoether compound of any one of claims 167-193, wherein R5is -CO2H or a structure:

195. The thioether or selenoether compound of any one of claims 167-194, wherein R5is-CO2H.

196. The thioether or selenoether compound of any one of claims 167-195, wherein R6is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

197. The thioether or selenoether compound of any one of claims 167-196, wherein R6is a glycine side chain.

198. The thioether or selenoether compound of any one of claims 167-197, wherein R7is a side chain of an amino acid selected from glycine and alanine.

199. The thioether or selenoether compound of any one of claims 167-198, wherein R7is an alanine side chain.

200. The thioether or selenoether compound of any one of claims 167-199, wherein R8is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, phenylalanine, tyrosine, and tryptophan.

201. The thioether or selenoether compound of any one of claims 167-200, wherein R8is an alanine side chain.

202. The thioether or selenoether compound of any one of claims 167-201, wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.

203. The thioether or selenoether compound of any one of claims 167-202, wherein Ar1is an unsubstituted 6-membered aryl.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 204. The thioether or selenoether compound of any one of claims 167-203, having a structure represented by the formula:

205. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

206. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by a formula selected from:

207. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1208. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

209. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

210. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

211. The thioether or selenoether compound of any one of claims 167-203, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 212. The thioether or selenoether compound of any one of claims 167-211, having the amino acid sequence GC1XANZ1A (SEQ ID NO: 9), wherein X is any amino acid, Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1.

213. The thioether or selenoether compound of any one of claims 167-212, having the amino acid sequence GC1XANZ1A (SEQ ID NO: 6), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

214. The thioether or selenoether compound of any one of claims 167-211, having the amino acid sequence YGC1XANZ1A (SEQ ID NO: 12), wherein X is any amino acid, Z is a peptoid-based amino acid residue capable of forming a intrapeptide thioether linkage, and a thioether crosslink extends from C1to Z1.

215. The thioether or selenoether compound of any one of claims 167-212, having the amino acid sequence YGC1XANZ1A (SEQ ID NO: 13), wherein X is sarcosine, Z is N-glutamate, and a thioether crosslink extends from C1to Z1.

216. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

217. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

218. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by a formula selected from:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1219. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

220. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

221. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 222. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by a formula selected from:

223. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

224. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

225. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1226. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

227. The thioether or selenoether compound of any one of claims 167-204, having a structure represented by the formula:

228. A thioether or selenoether compound having a structure represented by the formula:wherein each of m, n, and o is independently selected from 0 and 1, provided that when n is 1, then m is 1;wherein p is an integer selected from 0 to 50;wherein q is an integer selected from 0 to 20;wherein r is an integer selected from 0 to 500;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein s is selected from 1 and 2;wherein each of v and w is independently selected from 0 and 1, provided that when v is 0, then r is 0;wherein A is S or Se;wherein Q1is a leader sequence;wherein Q2is a cleavable moiety;wherein L is selected from C2-C4 alkyl, -(C1-C4 alkyl)(OCH2CH2)v’, and a structure selected from:wherein v’ is selected from 1, 2, 3, and 4;wherein Z is *-NH(CH2CH2O)w'CH2C(O)-**;wherein * denotes a bond connected to -Q2- and ** denotes a bond connected to the remainder of the compound;wherein w’ is selected from 1, 2, 3, 4, 5, and 6;wherein each occurrence of R1, R1’, and R1”, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, -(C1-C4)S(C1-C4 alkyl), -(C1-C4)C(O)NH2, -(C1-C4)Ar1, and Ar1and wherein each occurrence of R2, R2’, and R2”, when present, is independently a side chain of an amino acid,or wherein R1, R1’, or R1” is covalently bonded to R2, R2’, and R2”, respectively, and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle;wherein Ar1selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 wherein each of R3, R7, and R11is independently a side chain of an amino acid; wherein each of R4aand R4b, when present, is independently selected from hydrogen and C1-C4 alkyl;wherein R6is a side chain of an amino acid;wherein R10is selected from -CO2H, -SO2NH2, -SO3H, -NHC(O)NHSO2CH3, structure selected from:wherein R12is a side chain of amino acid, provided that the amino acid is not isoleucine, proline, or threonine; andwherein each of R13aand R13bis independently selected from C2-C5 alkynyl, C1-C5 azido, and a side chain of an amino acid.

229. The thioether or selenoether compound of claim 228, wherein each of m and n is 0.

230. The thioether or selenoether compound of claim 228, wherein m is 1.

231. The thioether or selenoether compound of any one of claims 228-230, wherein 0 is 0.

232. The thioether or selenoether compound of any one of claims 228-230, wherein o is 1.

233. The thioether or selenoether compound of any one of claims 228-232, wherein p is an integer from 0 to 25.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 234. The thioether or selenoether compound of any one of claims 228-233, wherein p is selected from 0, 1, 2, 3, 4, 5, and 6.

235. The thioether or selenoether compound of any one of claims 228-234, wherein p is selected from 0 and 1.

236. The thioether or selenoether compound of any one of claims 228-235, wherein r is 0.

237. The thioether or selenoether compound of any one of claims 228-236, wherein s is 1.

238. The thioether or selenoether compound of any one of claims 228-237, wherein each of r and v is 0.

239. The thioether or selenoether compound of any one of claims 228-238, wherein v is 1.

240. The thioether or selenoether compound of any one of claims 228-239, wherein w is 0.

241. The thioether or selenoether compound of any one of claims 228-239, wherein w is 1.

242. The thioether or selenoether compound of any one of claims 228-241, wherein A is S.

243. The thioether or selenoether compound of any one of claims 228-242, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1) or LKQINVIAGVKPIRAYG (SEQ ID NO: 2).

244. The thioether or selenoether compound of any one of claims 228-243, wherein Q1is LKQINVIAGVKEPIRAYG (SEQ ID NO: 1).

245. The thioether or selenoether compound of any one of claims 228-244, wherein Q2is *-CO2-(C4-C8 alkylene)-OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 246. The thioether or selenoether compound of any one of claims 228-245, wherein Q2is *-CO2CH2CH=CHCH2OC(O)-**, wherein * denotes a bond connected to Q1and ** denotes a bond connected to Z.

247. The thioether or selenoether compound of any one of claims 228-246, wherein Q2is a chemically cleavable moiety.

248. The thioether or selenoether compound of claim 247, wherein the chemically cleavable moiety is a protease recognition sequence.

249. The thioether or selenoether compound of claim 248, wherein the protease recognition sequence is a TEV recognition sequence.

250. The thioether or selenoether compound of claim 249, wherein the TEV protease recognition sequence is ENLYFQ (SEQ ID NO: 3).

251. The thioether or selenoether compound of any one of claims 228-250, wherein each of R1', R1’, and R1", when present, is independently selected from hydrogen, C1-C4 alkyl, 01-04 aminoalkyl, -(C1-O4)C(O)NH2, and -(C1-C4)Ar1.

252. The thioether or selenoether compound of any one of claims 228-251, wherein at least one of R1, R1’, and R1", when present, is not hydrogen.

253. The thioether or selenoether compound of any one of claims 228-252, wherein each of R1', R1’, and R1", when present, is hydrogen.

254. The thioether or selenoether compound of any one of claims 228-253, wherein R3is a side chain of an amino acid selected from cysteine, homocysteine, and selenocysteine.

255. The thioether or selenoether compound of any one of claims 228-254, wherein each of R3, R7, and R11is not a glycine side chain.

256. The thioether or selenoether compound of any one of claims 228-255, wherein each of R3, R7, and R11is a glycine side chain.

257. The any one of claims 228-256, wherein each of R4aand R4bis hydrogen.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 258. The thioether or selenoether compound of any one of claims 228-257, wherein R6is hydrogen.

259. The thioether or selenoether compound of any one of claims 228-258, wherein R7is a side chain of an amino acid selected from glycine and alanine.

260. The thioether or selenoether compound of any one of claims 228-259, wherein R7is an alanine side chain.

261. The thioether or selenoether compound of any one of claims 228-260, wherein R10is -CO2H or a structure:

262. The thioether or selenoether compound of any one of claims 228-261, wherein R10is -CO2H.

263. The thioether or selenoether compound of any one of claims 228-262, wherein R11is a side chain of an amino acid selected from glycine and alanine.

264. The thioether or selenoether compound of any one of claims 228-263, wherein R11is an alanine side chain.

265. The thioether or selenoether compound of any one of claims 228-262, wherein R11is not a glycine side chain.

266. The thioether or selenoether compound of any one of claims 228-265, wherein R12is a side chain of an amino acid selected from alanine, valine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, glycine, phenylalanine, tyrosine, and tryptophan.

267. The thioether or selenoether compound of any one of claims 228-266, wherein R12is a side chain of an amino acid selected from alanine, leucine, serine, cysteine, methionine, arginine, lysine, asparagine, and glycine.

268. The thioether or selenoether compound of any one of claims 228-267, wherein R12is a glycine side chain.SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 269. The thioether or selenoether compound of any one of claims 228-268, wherein each of R13aand R13bis independently selected -CCH, -CH2N3, and a side chain of an amino acid.

270. The thioether or selenoether compound of any one of claims 228-269, wherein Ar1is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.

271. The thioether or selenoether compound of any one of claims 228-270, wherein Ar1is an unsubstituted 6-membered aryl.

272. The thioether or selenoether compound of any one of claims 228-271, wherein the compound comprises one or more D-amino acid residues.

273. The thioether or selenoether compound of any one of claims 228-272, wherein the compound comprises one or more p-amino acid residues.

274. The thioether or selenoether compound of any one of claims 228-272, wherein the compound comprises one or more N-methylated amino acid residues.

275. The thioether or selenoether compound of any one of claims 228-274, having a structure represented by the formula:

276. The thioether or selenoether compound of any one of claims 228-275, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 277. The thioether or selenoether compound of any one of claims 228-275, having a structure represented by the formula:

278. The thioether or selenoether compound of any one of claims 228-275, having279. The thioether or selenoether compound of any one of claims 228-275, having a structure represented by the formula:

280. The thioether or selenoether compound of any one of claims 228-275, having a structure represented by the formula:SMRH Docket No. 214G-419841-WO BS Docket No. 21101.0490P1 281. The thioether or selenoether compound of any one of claims 228-275, having a structure represented by the formula:

282. The thioether or selenoether compound of any one of claims 228-275, having a structure represented by the formula:

283. The thioether or selenoether compound of any one of claims 228-275, having a structure represented by the formula:

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