Compositions of sulfonyl-purine compounds and use thereof for modifying functional protein sites

Abstract

Compounds comprising sulfonyl-purine or sulfonyl-purine analog bonds are described for use as electrophiles in sulfonyl-purine (SuPUR) chemistry. Also described is the use of SuPUR and / or SuPUR chemistry for proteome labeling of reactive amino acid residues and for developing new covalent therapeutic agents that selectively modify select amino acid residues (e.g., tyrosine or lysine residues) in biologically active proteins and peptides, such as amyloid-beta (Aβ)-binding alcohol dehydrogenase (ABAD), guanine nucleotide binding protein alpha stimulating activity polypeptide (GNAS), alpha / beta-hydrolase domain 10 (ABHD10), glutathione S-transferase pi 1 (GSTP1), glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1), poly(ADP-ribose) polymerase 2 (PARP2), and acetyl-CoA acetyltransferase 2 (ACAT2) proteins.

Description

[0001]Attorney Docket No.: 3436 / 3 PCT DESCRIPTION COMPOSITIONS OF SULFONYL-PURINE COMPOUNDS AND USE THEREOF FOR MODIFYING FUNCTIONAL PROTEIN SITES CROSS REFRENCE TO RELATED APPLICATION 5 This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 649,306, filed May 17, 2024, the disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The presently disclosed subject matter relates to sulfonyl-purine and sulfonyl-purine analog- 10 containing compounds, as well as to their use in covalently modifying peptides and proteins, in proteomics, and for modulating the biological activity of peptides and proteins. For example, these compounds, also referred to herein as sulfonyl-purine (SuPUR) ligands or probes, can form covalent conjugates with nucleophilic groups in peptides and proteins (e.g., with phenols and amines of tyrosine and lysine side chains), thereby forming covalently modified peptides and proteins. Exemplary 15 covalently modified proteins described include amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) and alpha / beta (^ / ^)-hydrolase domain 10 (ABHD10). BACKGROUND Alzheimer’s disease (AD) is the most common form of dementia. Currently, no cure exists, and available treatments only manage early symptoms. Mitochondrial dysfunction is a hallmark of beta- 20 amyloid (also known as amyloid-beta or Aβ) neurotoxicity. A^ is the pathological protein in AD, partly due to the interaction between Aβ and ABAD. ABAD is a mitochondrial protein that is an important regulator of energy balance and, upon Aβ binding, activates signaling cascades leading to neuronal death. One role of ABAD is maintaining the balance of estradiol / estriol in neurons. However, the Aβ- ABAD interaction disrupts this balance, resulting in decreased estradiol levels, increased reactive 25 oxygen species (ROS), and cell apoptosis. Two other proteins, peroxiredoxin-2, and annexin-1 are also implicated in the toxicity mediated by the Aβ-ABAD complex. ABHD10 is a member of the serine hydrolase superfamily and plays an important role in the metabolism of the immunosuppressant mycophenolate mofetil (MMF) by facilitating the removal of acyl glucuronide metabolite (AcMPAG) in the liver. This process detoxifies the body and reduces the 30 risk of MMF-induced side effects, such as leucopenia and gastrointestinal toxicity. ABHD10 also exhibits a similar detoxifying effect on probenecid acyl glucuronide (PRAG), the primary metabolite of the uricosuric agent probenecid, which can cause severe allergic or anaphylactic reactions. Additionally, ABHD10 has S-depalmitoylase activity, which acts on peroxiredoxin-5 (PRDX5), an important antioxidant protein. Therefore, ABHD10 can be classified as a member of the acyl protein 35 thioesterase (APT) family of regulatory proteins. So far, ABHD10 inhibitors have been reported to - 1 - Attorney Docket No.: 3436 / 3 PCT effectively inhibit its activity by covalently binding serine. However, these inhibitors can also display inhibitory activity to other serine hydrolase enzymes because of their conserved active site. Accordingly, there is an ongoing need for covalent probes and ligands for use in the investigation of the function of ABAD and ABHD10, as well as other proteins, and in the development 5 of therapeutic compounds that can modulate protein activity. In particular, there is an ongoing need for selective inhibitors of these proteins. SUMMARY This Summary lists several embodiments of the presently disclosed subject matter, and in many cases lists variations and permutations of these embodiments. This Summary is merely exemplary of 10 the numerous and varied embodiments. Mention of one or more representative features of a given embodiment is likewise exemplary. Such an embodiment can typically exist with or without the feature(s) mentioned; likewise, those features can be applied to other embodiments of the presently disclosed subject matter, whether listed in this Summary or not. To avoid excessive repetition, this Summary does not list or suggest all possible combinations of such features. 15 In some embodiments, the presently disclosed subject matter provides a compound having a structure of Formula (I): wherein: each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, 20 and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group consisting of H, O, F, Cl, Br,-NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R; and R is selected from -S(=O)2-R1and -CH2-S(=O)2-R1, where R1is selected from the group consisting of alkyl, 25 substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, R is -S(=O)2-R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, optionally wherein R1is selected from phenyl and substituted phenyl; or a 30 pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has a structure of Formula (II): - 2 - Attorney Docket No.: 3436 / 3 PCT Formula (II), wherein: Z is CH or N; Y is CH or N; X1and X2are independently selected from the group consisting of H, F, Cl, Br, -NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; and R1is selected from 5 the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, Z and Y are each N, and the compound of Formula (II) has a structure of Formula (II’): Formula (II’), 10 wherein: X1and X2are independently selected from the group consisting of -H, -NH2, -NHX5, and - N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)-H, -C(=O)- alkyl, and a nitrogen-protecting group, optionally where X1and X2are each H; and R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof. 15 In some embodiments, R1is phenyl or substituted phenyl, and the compound of Formula (II) has a structure of Formula (III): - 3 - Attorney Docket No.: 3436 / 3 PCT Formula (III), wherein: Z is CH or N; Y is CH or N; X1and X2are independently selected from the group consisting of H, F, Cl, Br, -NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of 5 alkyl, aralkyl, aryl, -C(=O)-H, -C(=O)-alkyl, and a nitrogen-protecting group; R2, R3, R4, R5, and R6are independently selected from the group consisting of H, cyano, halo, alkyl, perhaloalkyl, alkoxy, perhaloalkoxy, carboxyl, formyl, -C(=O)-R7, -NH-C(=O)-R7, and -C(=O)-N(R8)2; R7is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl; and each R8is independently selected from the group consisting of H, alkyl, substituted 10 alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, and substituted aralkyl; or where two R8groups together with the nitrogen to which they are attached form a substituted or unsubstituted nitrogen- containing heterocyclic ring; or a pharmaceutically acceptable salt thereof. In some embodiments, Z and Y are N, and the compound of Formula (III) has a structure of Formula (III’): Formula (III’), 15 wherein: X1and X2are independently selected from the group consisting of H, -NH2, F, Cl, Br, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, - C(=O)-alkyl, and a nitrogen-protecting group, optionally wherein X1and X2are each H; R2, R3, R4, R5, and R6are independently selected from the group consisting of H, cyano, halo, alkyl, perhaloalkyl, - 4 - Attorney Docket No.: 3436 / 3 PCT alkoxy, perhaloalkoxy, carboxyl, formyl, -C(=O)-R7, -NH-C(=O)-R7, and -C(=O)-N(R8)2; R7is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl; and each R8is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, and substituted aralkyl; or where two R8groups 5 together with the nitrogen to which they are attached form a substituted or unsubstituted nitrogen- containing heterocyclic ring; or a pharmaceutically acceptable salt thereof. In some embodiments, R2, R3, R4, R5, and R6are independently selected from the group consisting of H, cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, trifluoroalkoxy, methoxy, carboxyl, formyl, acetyl, -NH-C(=O)-alkyl, -C(=O)-NHR8, and 10 , wherein: R8is selected from terminal alkyne-substituted alkyl, cycloalkyl, cycloalkyl-substituted alkyl, aralkyl, and aryl; and R9is aralkyl. In some embodiments, one or both of R2and R6are selected from the group consisting of fluoro, chloro, bromo, methyl, perfluoromethyl, methoxy, and perfluoromethoxy. In some embodiments, R4is cyano. 15 In some embodiments, R is selected from the group consisting of: - 5 - Attorney Docket No.: 3436 / 3 PCT , - 6 - Attorney Docket No.: 3436 / 3 PCT - 7 - Attorney Docket No.: 3436 / 3 PCT 5 - 8 - Attorney Docket No.: 3436 / 3 PCT In some embodiments, the presently disclosed subject matter provides a pharmaceutical composition comprising a compound having a structure of Formula (I) and a pharmaceutically acceptable carrier. In some embodiments, the presently disclosed subject matter provides a method of covalently 5 modifying a peptide or protein, the method comprising contacting a sample comprising the peptide or protein with a compound of Formula (I) or a pharmaceutical composition thereof. In some embodiments, the contacting provides a covalent modified peptide or protein, wherein said covalently modified peptide or protein comprises one or more covalently modified tyrosine or covalently modified lysine residues, wherein the covalently modified tyrosine or covalently modified lysine residues 10 comprise a structure: wherein R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, 15 optionally wherein R1is selected from phenyl and substituted phenyl. In some embodiments, covalently modifying the peptide or protein modulates one or more biological activity of said peptide or protein. In some embodiments, the peptide or protein is selected from the group consisting of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD), guanine nucleotide binding protein alpha stimulating activity polypeptide (GNAS), and alpha / beta-hydrolase 20 domain 10 (ABHD10). In some embodiments, the sample comprising the peptide or protein is selected from the group consisting of a biological fluid, a cell extract, a cell, a tissue, an organ, and an organism. In some embodiments, the presently disclosed subject matter provides a method of inhibiting amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD), the method comprising contacting a sample comprising ABAD with a compound of Formula (I), thereby covalently modifying one or more 25 amino acid residues in the ABAD, wherein the compound of Formula (I) has a structure: - 9 - Attorney Docket No.: 3436 / 3 PCT Formula (I), wherein: each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group 5 consisting of H, O, F, Cl, Br,-NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; and X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R, and R is - S(=O)2-R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted 10 heteroaryl; or a pharmaceutically acceptable salt thereof; optionally wherein Z and Y are each selected from N and NH. In some embodiments, R is selected from the group consisting of: ,, - 10 - Attorney Docket No.: 3436 / 3 PCT In some embodiments, R is: . In some embodiments, the covalently modified ABAD comprises a covalently modified non- catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is 5 tyrosine 168 (Tyr168). In some embodiments, the covalently modified ABAD exhibits reduced catalytic activity compared to a corresponding unmodified ABAD. In some embodiments, the covalently modified ABAD exhibits decreased binding for beta-amyloid (A^) compared to a corresponding unmodified ABAD. In some embodiments, the covalently modified ABAD exhibits a reduction in reactive oxygen species (ROS) induced by beta-amyloid (A^) compared to a corresponding 10 unmodified ABAD. In some embodiments, the presently disclosed subject matter provides a method of inhibiting alpha / beta-hydrolase domain 10 (ABHD10), the method comprising contacting a sample comprising ABHD10 with a compound of Formula (I), thereby covalently modifying one or more amino acid residues in the ABHD10, wherein the compound has a structure of Formula (I): 15 Formula (I), wherein: each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group consisting of H, O, F, Cl, Br,-NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group 20 consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; and X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R, and R is - S(=O)2-R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted - 11 - Attorney Docket No.: 3436 / 3 PCT heteroaryl; or a pharmaceutically acceptable salt thereof, optionally wherein Y and Z are each selected from N and NH. In some embodiments, R is selected from the group consisting of: , 5 - 12 - Attorney Docket No.: 3436 / 3 PCT In some embodiments, R is: In some embodiments, the covalently modified ABHD10 comprises a covalently modified non- catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is 5 tyrosine 215 (Tyr215). In some embodiments, the covalently modified ABHD10 exhibits reduced catalytic activity compared to a corresponding unmodified ABHD10. In some embodiments, the presently disclosed subject matter provides a method of identifying a reactive amino acid residue of a protein, optionally wherein the reactive amino acid residue is a tyrosine residue or a lysine residue, the method comprising: (a) providing a protein sample comprising 10 isolated proteins, living cells, or a cell lysate; (b) contacting the protein sample with a probe compound for a period of time sufficient for the probe compound to covalently react with at least one reactive amino acid residue in the protein sample, thereby forming at least one modified reactive amino acid residue; and (c) analyzing proteins in the protein sample to identify at least one modified reactive amino acid residue, thereby identifying at least one reactive amino acid residue of a protein; wherein the probe 15 compound has a structure of Formula (I): Formula (I), wherein: each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group 20 consisting of H, O, F, Cl, Br,-NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; and X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R, and R is selected from -S(=O)2-R1, where R1is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl and substituted heteroaryl, wherein said - 13 - Attorney Docket No.: 3436 / 3 PCT substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl or substituted heteroaryl comprises at least one substituent comprising a terminal alkyne moiety, a fluorophore, or a detectable tag; and wherein the at least one modified reactive amino acid residue comprises a structure -S(=O)2- R1. In some embodiments, Y and Z are each selected from N and NH. 5 Accordingly, it is an object of the presently disclosed subject matter to provide compounds of Formula (I), e.g., SuPUR compounds, related pharmaceutical compositions, methods of identifying reactive amino acid residues, and methods of covalently modifying peptides and proteins, e.g., ABAD and ABHD10. This and other objects are achieved in whole or in part by the presently disclosed subject matter. 10 An object of the presently disclosed subject matter having been stated above, other objects and advantages of the presently disclosed subject matter will become apparent to those of ordinary skill in the art after a study of the following description of the presently disclosed subject matter and non- limiting Figures and Examples. BRIEF DESCRIPTION OF THE FIGURES 15 The presently disclosed subject matter will now be described more fully hereinafter with reference to the accompanying Figures, in which representative embodiments are shown. The presently disclosed subject matter can, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the embodiments to those 20 skilled in the art. Certain components in the Figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the presently disclosed subject matter (in some cases schematically). Figure 1A is a schematic drawing comparing generic chemical structures of, from left to right, sulfonyl-fluoride compounds used in sulfonyl-fluoride exchange (SuFEx) chemistry, sulfonyl-triazole 25 compounds used in sulfonyl-triazole exchange (SuTEx) chemistry, and exemplary sulfonyl-purine compounds for use in sulfonyl-purine (SuPUR) chemistry. The leaving groups of these compounds upon reaction with a nucleophilic moiety are F, triazole, and purine, respectively. R1in each of the compounds represents a sulfonyl substituent that remains attached with the sulfonyl group to a nucleophilic moiety (e.g., a nucleophilic moiety of a peptide or protein) covalently modified by the 30 SuFEx, SuTEx, or SuPUR compound. In the sulfonyl-triazole compound, one of X and Y is N and the other is CH. R2represents a substituent attached to the triazole leaving group. Figure 1B is a schematic drawing showing the chemical structure of an exemplary sulfonyl- purine (SuPUR) probe compound referred to herein as “AHL-PuP-2”. Figure 1C is a schematic drawing showing the chemical structure of an exemplary sulfonyl- 35 purine (SuPUR) ligand compound referred to herein as “ZH-2-049-2”. - 14 - Attorney Docket No.: 3436 / 3 PCT Figure 1D is a schematic drawing showing an exemplary workflow for sulfonyl-purine (SuPUR)-based proteomic studies. Figure 1E is an image of a gel from a gel-based activity-based protein profiling (APBB) assay performed in the cell soluble fraction (left) and the membrane soluble fraction of cells using sulfonyl- 5 purine (SuPUR) chemistry. The concentrations noted on the top of the gel image refer to the micromolar (^M) concentration of the SuPUR probe (i.e., the AHL-PuP-2 probe shown in Figure 1B) used in the assay. Figure 1F is a graph showing the combined liquid chromatography-tandem mass spectrometry (LC-MS / MS) data from in vitro proteome labeling using a sulfonyl-purine (SuPUR) probe (i.e., the 10 AHL-PuP-2 probe shown in Figure 1B). The graph at the two shows the total number of modified residues for each type of amino acid residue based on quality peptide-spectrum matches (PSMs). The total number of proteins labeled was 1800 and the total number of quality peptides was 9905. 40.39% of the labeled peptides were labeled at a lysine (Lys or K) residue, while 55.41% of the labeled peptides were labeled at a tyrosine (Tyr or Y) residue. 15 Figure 2A is an image of portions of a gel assay of the cell soluble fraction of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD)-transfected HEK-293 cells incubated first with dimethyl sulfoxide (DMSO) or 2.5 micromolar (^M), 25 ^M, 100 ^M, or 200 ^M of an exemplary sulfonyl- purine (SuPUR) ligand (referred to herein as “ZH-2-049-2”) and then with a SuPUR probe (referred to herein as “AHL-PuP-2”) for one hour. The top portion of the figure shows that the ABAD band 20 decreases in a sulfonyl-purine ligand concentration-dependent manner, indicating that ABAD reacts with the ligand in a concentration-dependent manner, thereby blocking reaction with the probe. Figure 2B is an image of portions of a gel assay showing that the sulfonyl-purine (SuPUR) probe compound reacts with wild-type (WT) amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD), but not with a mutant ABAD where the tyrosine at residue 168 is replaced by a glycine 25 (Y168G). Figure 2C is a graph comparing the activity of wild-type (WT) amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) and the mutant ABAD where the tyrosine at residue 168 is replaced by glycine (Y168G). Activity was determined using a bioluminescent assay (sold under the tradename NAD-GLO™). 30 Figure 3A is a schematic drawing showing the structure of exemplary sulfonyl-purine (SuPUR) compounds assayed for binding to amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD). Figure 3B is a schematic drawing showing select residues in the catalytic pocket of amyloid- beta (A^)-binding alcohol dehydrogenase (ABAD), including tyrosine-168 (Tyr168), lysine-172 (Lys172), phenylalanine-201 (Phe201) with an exemplary sulfonyl-purine (SuPUR) ligand (ZH-2-049- 35 2) in the pocket and possible non-covalent interactions between the catalytic pocket residues and the ligand. - 15 - Attorney Docket No.: 3436 / 3 PCT Figure 3C is an image of portions of a gel showing gel-based sulfonyl-purine (SuPUR) assay results for reaction of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) with the different exemplary SuPUR ligands, i.e., ZH-1-049-2, ZH-2-025, and ZH-2-029. The chemical structures of the SuPUR ligands are shown at the top. 5 Figure 3D is a graph showing the ratio of the quantified fluorescence signal corresponding to the amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) band compared to the quantified fluorescence signal corresponding to a control protein band (^-FLAG) in the gel shown in Figure 3C. Figure 3E is a graph showing the concentration-dependent inhibition of amyloid-beta (A^)- binding alcohol dehydrogenase (ABAD) provided by exemplary sulfonyl-purine (SuPUR) compounds 10 ZH-1-049-2 (data in circles), ZH-2-025 (data in squares), and ZH-2-029 (data in triangles). Inhibition is expressed as a percentage compared ABAD not treated with a SuPUR compound and the concentration of the SuPUR compound is expressed as the log of the micromolar (^M) concentration of the compound. ZH-2-025 shows potent activity for ABAD with a 50% inhibitory concentration (IC50) of 430 nanomolar (nM). ZH-1-049-2 shows an IC50of 776 nM and ZH-2-029 an IC50of 571 nM. 15 Figure 4A is a schematic drawing showing select residues in the catalytic pocket of amyloid- beta (A^)-binding alcohol dehydrogenase (ABAD), including tyrosine-168 (Tyr168), lysine-172 (Lys172), alanine-154(Ala154), glycine-199 (Gly199), glycine-93 (Gly93), and phenylalanine-201 (Phe201) with an exemplary dichlorophenyl-substituted sulfonyl-purine (SuPUR) ligand (ZH-2-025) in the pocket and possible non-covalent interactions between the catalytic pocket residues and the ligand, 20 including possible halogen bonding interactions between the chloride atoms of the ligand and Gly93. Figure 4B is a schematic drawing showing the chemical structures of various sulfonyl-purine (SuPUR) ligands comprising ortho-substituted phenyl sulfonyl substituents. Figure 4C is an image of portions of a gel-based screening assay showing the amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) reactivity of the sulfonyl-purine (SuPUR) ligands shown 25 in Figure 4B. ZH-2-025, ZH-2-085, ZH-2-093, and ZH-2-101 showed the highest activity. Figure 4D is a graph showing the results of a bioluminescent screening assay (sold under the tradename NAD-GLO™) for the activity of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) treated with 500 nanomolar (nM) concentrations of exemplary sulfonyl-purine (SuPUR) compounds. 30 Figure 4E is a series of schematic drawings showing the chemical structures of three exemplary sulfonyl-purine (SuPUR) ligands containing dihalophenyl moieties and their calculated electrostatic potential (ESP) surfaces. ESP surfaces were calculated at the M062X / def2TZVPP level of theory by Gaussian 16 C.02 software. Multiwfn 3.8 program was utilized to evaluate the ESP surfaces and the ESP maps were plotted using the VMD 1.9 program. - 16 - Attorney Docket No.: 3436 / 3 PCT Figure 5A is a graph showing the results of a bioluminescent assay for nicotinamide adenine dinucleotide (NAD) (sold under the tradename NAD-GLO™) showing that NAD+ is a substrate of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD). Figure 5B is a graph showing the ability of exemplary sulfonyl-purine (SuPUR) ligands to 5 inhibit amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) binding to nicotinamide adenine dinucleotide (NAD+) as determined via a bioluminescent assay (sold under the tradename NAD- GLO™). The 50% inhibitory concentration (IC50) of ZH-2-025, ZH-2-029, ZH-2-101, and ZH-2-115 was 53.7 nanomolar (nM), 164.8 nM, 72.8 nM, and 706.3 nM, respectively. Figure 5C is a composite image of a gel showing the results of an assay determining the ability 10 of a sulfonyl-purine (SuPUR) ligand (ZH-2-025) to disrupt the interaction of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) and amyloid-beta 1-42 (A^ 1-42). Figure 5D is a graph showing the quantification of relevant protein signal compared to lane Input for the different gel lanes of the output side of the gel shown in Figure 5C. Figure 5E is a graph of results of a cell proliferation assay (WST-1 assay) showing the cell 15 toxicity of sulfonyl-purine (SuPUR) ligand ZH-2-025 in HEK293T and SH-SY5Y cells. A similar compound, ZH-2-036, did not display cell toxicity at the same concentrations used for ZH-2025. Figure 5F is a composite image of a gel showing the results of a pull down assay showing that exemplary sulfonyl-purine (SuPUR) ligand ZH-2-029 can disrupt the interaction between amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) and amyloid-beta 1-42 (A^ 1-42). 20 Figure 5G is a graph of results of a cell proliferation assay (WST-1 assay) showing that exemplary sulfonyl-purine (SuPUR) ligand ZH-2-029 exhibits moderate cell toxicity. Figure 5H is a composite gel image of cellular thermal shift assay (SETSA) showing that exemplary sulfonyl-purine (SuPUR) ligand ZH-2-029 can stabilize amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD), particularly for the dimer. 25 Figure 5I is a series of micrograph images of reactive oxygen species (ROS) production in cells treated under different conditions (i.e., sulfonyl-purine (SuPUR) compound ZH-2-029 and amyloid- beta 1-42 (A^ 1-42), SuPUR compound ZH-2-036 and A^ 1-42; A^ 1-42, or dimethyl sulfoxide (DMSO, control)). The non-fluorescent probe dichlorodihydrofluorescein diacetate (H2DCF-DA) was used to measure cytosolic ROS, e.g., hydrogen peroxide. See top row. To determine levels of the 30 superoxide anion radicals DHE was used, which is oxidized to the fluorescent ethidium cation by O2radical. See bottom row. For detection of mitochondria-associated ROS, dihydrorhodamine (DHR), which localized to the mitochondria. See middle row. Figure 6 is an image of a gel assay of the cell soluble and cell membrane fractions of HEK-293 cells treated with a sulfonyl-purine (SuPUR) ligand (ZH-1-049-2) for one hour at 0.02, 0.2, 2.0, 10, 50, 35 or 100 micromolar (^M) concentrations and then treated with 1 ^M fluorescently-tagged - 17 - Attorney Docket No.: 3436 / 3 PCT fluorophosphate (FP-Rh) for one hour. The SuPUR ligand showed selective labelling activity for ABHD10 in the membrane fraction. Figure 7A is a schematic diagram showing the chemical structures of some exemplary sulfonyl- purine (SuPUR) ligands assayed for ability to covalently modify and inhibit alpha / beta (^ / ^)-hydrolase 5 domain 10 (ABHD10). Figure 7B is an image of gel analysis of the screening of sulfonyl-purine (SuPUR) ligand activity in the cell membrane fraction of HEK-293 cells. The cell membrane fraction was treated with the SuPUR ligand indicated at the top of the image at a 0.2 micromolar (^M) or 2 ^M concentration for one hour and then with 1 ^M fluorescently-tagged fluorophosphate (FP-Rh) for one hour. 10 Figure 7C is an image of gel analysis of the screening of sulfonyl-purine (SuPUR) ligand activity in the cell soluble fraction of HEK-293 cells. The cell soluble fraction was treated with the SuPUR ligand indicated at the top of the image at a 0.2 micromolar (^M) or 2 ^M concentration for one hour and then with 1 ^M fluorescently-tagged fluorophosphate (FP-Rh) for one hour. Figure 8A is an image of a gel showing the concentration-dependent activity of exemplary 15 sulfonyl-purine (SuPUR) ligands ZH-2-097 and ZH-2-103 in a cell soluble fraction of HEK-293 cells. The cell soluble fraction (1 milligram / milliliter (mg / mL)) was treated with the SuPUR compound for 1 hour at 37°C and then with 1 micromolar (^M) fluorescently tagged fluorophosphate (FP-Rh) for one hour. Figure 8B is a graph showing the relationship between sulfonyl-purine (SuPUR) ligand 20 concentration (log of the micromolar (^M) ligand concentration) and the percentage (%) of alpha / beta (^ / ^)-hydrolase domain 10 (ABHD10) inhibition determined via gel-based screening in a cell soluble fraction of HEK-293 cells. Data is provided for ZH-2-097 (circles) and ZH-20103 (squares). Both compounds showed selective labeling activity for ABHD10. ZH-2-097 had a 50% inhibitory concentration (IC50) of 26.5 nanomolar (nM) and ZH-2-103 had an IC50of 29.2 nM. 25 Figure 8C is a schematic drawing showing the chemical structures of exemplary sulfonyl-purine (SuPUR) ligands: ZH-2-025, ZH-2-097, and ZH-2-103. Figure 8D is an image of a gel showing the concentration-dependent activity of exemplary sulfonyl-purine (SuPUR) ligands ZH-2-025, ZH-2-097, and ZH-2-103 in the membrane soluble fraction of HEK-293 cells. Cells were treated with the SuPUR compound for 2 hours and then with 1 micromolar 30 (^M) fluorescently tagged fluorophosphate (FP-Rh) for one hour. Figure 9A is a schematic drawing showing the chemical structures of exemplary sulfonyl- purine (SuPUR) ligands: ZH-2-097 and ZH-2-036. Figure 9B is a schematic drawing showing select residues in the catalytic pocket of alpha / beta (^ / ^)-hydrolase domain 10 (ABHD10), including tyrosine-215 (Tyr215), serine-152 (Ser152), serine- 35 86 (Ser86), histidine-279 (His279), arginine-280 (Arg280), and arginine-282 (Arg-282) with an - 18 - Attorney Docket No.: 3436 / 3 PCT exemplary an sulfonyl-purine (SuPUR) ligand, ZH-2-097 in the pocket and with possible interactions between the catalytic pocket residues and the ligand shown in dashed lines. Figure 9C is an image of a gel showing the concentration-dependent activity of exemplary sulfonyl-purine (SuPUR) ligands ZH-2-097 and ZH-2-103 in the membrane and soluble fractions of 5 HEK-293 cells. Cells were treated with the SuPUR compound for 2 hours and then with 1 micromolar (^M) fluorescently tagged fluorophosphate (FP-Rh) for one hour. Figure 10A is a heat map of hydrolase proteins modified by an exemplary sulfonyl-purine (SuPUR) compound ZH-2-097 (0.2 micromolar (^M), 2 ^M, 5 ^M or 10 ^M). For comparison, data for ZH-2-036, which has an imidazopyridine leaving group is shown at the bottom. 10 Figure 10B is a graph showing the abundance ratio of peptide-spectrum matches (PSMs) detected from particular amino acid residue ranges in alpha / beta (^ / ^)-hydrolase domain 10 (ABHD10) following covalent modification of ABHD10 with exemplary sulfonyl-purine (SuPUR) compound ZH- 2-097 at different concentrations (0.2 micromolar (^M), 2 ^M, 5 ^M or 10 ^M). For comparison, data is also shown for ABHD10 modified with ZH-2-036, which has an imidazopyridine leaving group is 15 shown. Figure 10C is a graph showing the one-way ANOVA analysis of the data shown in Figure 10B. Figure 10D is a schematic drawing showing a Venn diagram of overlapping hydrolase proteins detected based on activity-based protein profiling studies performed in cell membrane and cell soluble studies performed with exemplary sulfonyl-purine (SuPUR) ligand ZH-2-097. 20 Figure 10E is a graph showing the abundance ratio of peptide-spectrum matches (PSMs) detected from studies used to identify the binding site of exemplary sulfonyl-purine (SuPUR) compound ZH-2-097 in alpha / beta (^ / ^)-hydrolase domain 10 (ABHD10). ZH-2-097 showed selective labeling of ABHD10 at tyrosine-87 (Y87) and tyrosine-215 (Y215) in a concentration dependent manner. Figure 11 is an MS2 spectrum annotation of AHL-PuP-2 labeled site (Y380) found in a Keratin, 25 type I cytoskeletal 18 (KRT18) polypeptide (see e.g., Accession No. P05783 of the GENBANK® biosequence database). Figures 12A-12C are the results of analysis showing SuPUR chemistry mediates regio-selective protein-ligand interactions across the human proteome. Figure 12A shows the number of modified tyrosine (Y) and lysine (K) sites identified in the HEK293T proteome using AHL-PuP-2 (100 µM, 1 h, 30 rt; left panel) or ZH-2-087 (100 µM, 1 h, rt; right panel). Figure 12B is a bar graph (top) showing a comparison of AHL-PuP-2 modified sites and ZH-2-087 modified sites. Below the bar graph is a summary of the modified amino acids with each SuPUR ligand. Figure 12C is an overlay analysis of AHL-PuP-2 and ZH-2-087 labeled proteins (N = 3). Figure 13 is two plots of13C NMR data for ZH-1-049-2 and ZH-2-055 showing significant 35 chemical shifts in the C5 and C4 signals between the N9- and N7-substituted products, attributed to differences in electronic density. - 19 - Attorney Docket No.: 3436 / 3 PCT Figures 14A and 14B are volcano plots of SuPUR TMT-ABPP analysis of ZH-1-049-2 and ZH-2-036 (25 µM, 1 hour, in vitro) using AHL-PuP-2 as a probe and showing the distribution of probe- modified peptides in comparison between the compound-treated group and DMSO group in HEK293T soluble proteome (Figure 14A) and membrane proteome (Figure 14B). The data shown are 5 representative of three biologically independent experiments (n = 3). Figures 14C and 14D are volcano plots of SuPUR TMT-ABPP analysis of ZH-2-055 and ZH- 5-019 (25 µM, 1 hour, in vitro) using ZH-2-087 as a probe showing the distribution of probe-modified peptides in comparison between the compound-treated group and DMSO group in HEK293T soluble proteome (Figure 14C) and membrane proteome (Figure 14D). The data shown are representative of 10 three biologically independent experiments (N =3). Figure 15 is a proposed mechanism of ABHD10 inhibition by ZH-2-097 that involves covalent targeting a non-catalytic tyrosine, Tyr215. Figure 16 is a heatmap showing LC-MS / MS analysis of HEK293T cells treated with ZH-2-097 (0.2 µM-10 µM) and ZH-2-036 (control) versus DMSO revealing selective inhibition of ABHD10 in 15 serine hydrolase family. Figures 17A and 17B are volcano plots showing the distribution of probe modified peptides in comparison between compound treated group and DMSO group in soluble (Figure 17A) and membrane (Figure 17B) proteomes from HEK293T cells. Figure 18 is a gel showing the results of gel-based ABPP of SuPUR analogs that were designed 20 by a nitrogen-walk strategy and the binding activities thereof analogs. DETAILED DESCRIPTION The presently disclosed subject matter will now be described more fully hereinafter with reference to the accompanying Figures and Examples, in which representative embodiments are shown. The presently disclosed subject matter can, however, be embodied in different forms and should not be 25 construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the embodiments to those skilled in the art. Certain components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the presently disclosed subject matter (in some cases schematically). 30 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently described subject matter belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Throughout the specification and claims, a given chemical formula or name shall encompass 35 all active optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist. - 20 - Attorney Docket No.: 3436 / 3 PCT I. Definitions The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the presently disclosed subject matter. While the following terms are believed to be well understood by one of ordinary skill in the art, 5 the following definitions are set forth to facilitate explanation of the presently disclosed subject matter. Following long-standing patent law convention, the terms “a”, “an”, and “the” refer to “one or more” when used in this application, including in the claims. For example, the phrase “a protein” refers to one or more proteins, including a plurality of the same protein. Similarly, the phrase “at least one”, when employed herein to refer to an entity, refers to, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 10 30, 35, 40, 45, 50, 75, 100, or more of that entity, including but not limited to whole number values between 1 and 100 and greater than 100. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. The term “about”, as used herein when referring to a measurable value 15 such as an amount of mass, weight, time, volume, concentration, or percentage, is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1 % from the specified amount, as such variations are appropriate to perform the disclosed methods and / or employ the disclosed compositions. Accordingly, unless indicated to the contrary, the numerical parameters set 20 forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter. As used herein, the term “and / or” when used in the context of a list of entities, refers to the entities being present singly or in combination. Thus, for example, the phrase “A, B, C, and / or D” includes A, B, C, and D individually, but also includes any and all combinations and subcombinations 25 of A, B, C, and D. The term “comprising”, which is synonymous with “including” “containing”, or “characterized by”, is inclusive or open-ended and does not exclude additional, unrecited elements and / or method steps. “Comprising” is a term of art that means that the named elements and / or steps are present, but that other elements and / or steps can be added and still fall within the scope of the relevant subject 30 matter. As used herein, the phrase “consisting essentially of” limits the scope of the related disclosure or claim to the specified materials and / or steps, plus those that do not materially affect the basic and novel characteristic(s) of the disclosed and / or claimed subject matter. For example, a pharmaceutical composition can “consist essentially of” a pharmaceutically active agent or a plurality of 35 pharmaceutically active agents, which means that the recited pharmaceutically active agent(s) is / are the only pharmaceutically active agent(s) present in the pharmaceutical composition. It is noted, however, - 21 - Attorney Docket No.: 3436 / 3 PCT that carriers, excipients, and / or other inactive agents can and likely would be present in such a pharmaceutical composition and are encompassed within the nature of the phrase “consisting essentially of”. As used herein, the phrase “consisting of” excludes any element, step, or ingredient not 5 specifically recited. It is noted that, when the phrase “consists of” appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. With respect to the terms “comprising”, “consisting of”, and “consisting essentially of”, where one of these three terms is used herein, the presently disclosed and claimed subject matter can include 10 the use of either of the other two terms. For example, a composition that in some embodiments comprises a given active agent also in some embodiments can consist essentially of that same active agent, and indeed can in some embodiments consist of that same active agent. The terms “additional therapeutically active compound” and “additional therapeutic agent”, as used in the context of the presently disclosed subject matter, refers to the use or administration of a 15 compound for an additional therapeutic use for a particular injury, disease, or disorder being treated. Such a compound, for example, could include one being used to treat an unrelated disease or disorder, or a disease or disorder which may not be responsive to the primary treatment for the injury, disease, or disorder being treated. As used herein, the terms “administration of” and / or “administering” a compound should be 20 understood to refer to providing a compound of the presently disclosed subject matter to a subject in need of treatment. The term “aqueous solution” as used herein can include other ingredients commonly used, such as sodium bicarbonate described herein, and further includes any acid or base solution used to adjust the pH of the aqueous solution while solubilizing a peptide. 25 The term “binding” refers to the adherence of molecules to one another, such as, but not limited to, enzymes to substrates, ligands to receptors, antibodies to antigens, DNA binding domains of proteins to DNA, and DNA or RNA strands to complementary strands. “Binding partner”, as used herein, refers to a molecule capable of binding to another molecule. The term “biocompatible”, as used herein, refers to a material that does not elicit a substantial 30 detrimental response in the host. As used herein, the terms “biologically active fragment” and “bioactive fragment” of a peptide encompass natural and synthetic portions of a longer peptide or protein that are capable of specific binding to their natural ligand and / or of performing a desired function of a protein, for example, a fragment of a protein of larger peptide which still contains the epitope of interest and is immunogenic. 35 The term “biological sample”, as used herein, refers to samples obtained from a subject, including but not limited to skin, hair, tissue, blood, plasma, cells, sweat, and urine. - 22 - Attorney Docket No.: 3436 / 3 PCT A “control” cell, tissue, sample, or subject is a cell, tissue, sample, or subject of the same type as a test cell, tissue, sample, or subject. The control may, for example, be examined at precisely or nearly the same time the test cell, tissue, sample, or subject is examined. The control may also, for example, be examined at a time distant from the time at which the test cell, tissue, sample, or subject is 5 examined, and the results of the examination of the control may be recorded so that the recorded results may be compared with results obtained by examination of a test cell, tissue, sample, or subject. The control may also be obtained from another source or similar source other than the test group or a test subject, where the test sample is obtained from a subject suspected of having a condition, disease, or disorder for which the test is being performed. 10 A “test” cell is a cell being examined. A “pathogenic” cell is a cell that, when present in a tissue, causes or contributes to a condition, disease, or disorder in the animal in which the tissue is located (or from which the tissue was obtained). A tissue “normally comprises” a cell if one or more of the cell are present in the tissue in an animal not afflicted with a condition, disease, or disorder. 15 As used herein, the terms “condition”, “disease condition”, “disease”, “disease state”, and “disorder” refer to physiological states in which diseased cells or cells of interest can be targeted with the compositions of the presently disclosed subject matter. As used herein, the term “diagnosis” refers to detecting a risk or propensity to a condition, disease, or disorder. In any method of diagnosis exist false positives and false negatives. Any one 20 method of diagnosis does not provide 100% accuracy. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence 25 of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. As used herein, an “effective amount” or “therapeutically effective amount” refers to an amount of a compound or composition sufficient to produce a selected effect, such as but not limited to alleviating symptoms of a condition, disease, or disorder. In the context of administering compounds in 30 the form of a combination, such as multiple compounds, the amount of each compound, when administered in combination with one or more other compounds, may be different from when that compound is administered alone. Thus, an effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amounts of each compound may vary. The term “more effective” means that the selected effect occurs to a greater extent by one treatment 35 relative to the second treatment to which it is being compared. - 23 - Attorney Docket No.: 3436 / 3 PCT As used herein, an “essentially pure” preparation of a particular protein or peptide is a preparation wherein in some embodiments at least about 95% and in some embodiments at least about 99%, by weight, of the protein or peptide in the preparation is the particular protein or peptide. In some embodiments, the terms “fragment”, “segment”, or “subsequence” as used herein refers 5 to a portion of an amino acid sequence, comprising at least one amino acid, or a portion of a nucleic acid sequence comprising at least one nucleotide. Thus, in some embodiments, the terms “fragment”, “segment”, and “subsequence” are used interchangeably herein. The phrase “sulfonyl-purine (SuPUR)” (or “SuPUR compound”) as used herein refers to a synthetic compound that includes a sulfonyl group directly attached to a nitrogen atom of a purine 10 moiety or a purine analog moiety (e.g., another bicyclic, imidazole-containing fused ring moiety, such as a hypoxanthine, xanthine, imidazopyridine, or benzimidazole moiety). The purine or purine analog moiety can be substituted or unsubstituted. Typically, a SuPUR compound can undergo SuPUR chemistry, e.g., in which the sulfonyl group of the SuPUR compound acts as an electrophile in a covalent reaction between the SuPUR compound and a reactive nucleophilic group of another 15 compound, such as a reactive amino acid residue in a protein or peptide. SuPUR compounds disclosed herein can include SuPUR “ligands” and SuPUR “probes.” As used herein, the terms “SuPUR probe” or “probe” can refer to a SuPUR compound that is broadly reactive and can be used to detect sites amenable to covalent reactions with SuPUR compounds. SuPUR probes can include a tag for detection. The tag for detection can be a moiety that can be directly 20 used for detection (e.g., a fluorophore, biotin or another affinity label, a radioisotope, etc.) or a moiety (e.g., an alkyne group) that can be chemically modified to incorporate a detectable group (e.g., biotin) after the SuPUR probe has undergone a covalent reaction with a SuPUR reactive site. In contrast, the terms “SuPUR ligand” or “ligand”, as used herein, can refer to a SuPUR compound that does not include a tag for detection and / or that has been tailored to undergo covalent reactions more selectively 25 with a particular reactive site and / or protein and / or peptide of interest. For example, the selectivity of a SuPUR ligand can be tailored via the addition of substituents that can alter the reactivity of the SuPUR compound via steric or electronic effects. In some embodiments, the SuPUR ligands can be used for the development of therapeutic agents that target and / or modulate the activity of one or more particular biological molecules of interest. 30 Thus, as used herein, in some embodiments, “ligand” can refer to a synthetic molecule (e.g., a SuPUR compound) that binds to a target compound or molecule, such as a reactive nucleophilic amino acid residue in a peptide or protein. In some embodiments, as can be determined by one of ordinary skill in the art based on context, the term “ligand” as used herein can be used more generally to refer to any entity (e.g., a molecule) that specifically or selectively binds to or “is specifically or selectively 35 reactive with a second entity (e.g., a biomolecule, such as a peptide, protein, nucleic acid, lipid, etc.) when the ligand functions in a binding reaction which is determinative of the presence of the second - 24 - Attorney Docket No.: 3436 / 3 PCT entity in a heterogenous sample (i.e., a sample comprising a plurality of different entities, such as a plurality of different biomolecules). As used herein, a “functional” biological molecule is a biological molecule in a form in which it exhibits a property by which it can be characterized. A functional enzyme, for example, is one that 5 exhibits the characteristic catalytic activity by which the enzyme can be characterized. As used herein “injecting”, “applying”, and administering” include administration of a compound of the presently disclosed subject matter by any number of routes and modes including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, 10 sublingual, vaginal, ophthalmic, pulmonary, vaginal, and rectal approaches. As used herein, the term “linkage” refers to a connection between two groups. The connection can be either covalent or non-covalent, including but not limited to ionic bonds, hydrogen bonding, and hydrophobic / hydrophilic interactions. As used herein, the term “linker” refers to a molecule that joins two other molecules either 15 covalently or noncovalently, such as but not limited to through ionic or hydrogen bonds or van der Waals interactions. The terms “measuring the level of expression” and “determining the level of expression” as used herein refer to any measure or assay which can be used to correlate the results of the assay with the level of expression of a gene or protein of interest. Such assays include measuring the level of 20 mRNA, protein levels, etc. and can be performed by assays such as northern and western blot analyses, binding assays, immunoblots, etc. The level of expression can include rates of expression and can be measured in terms of the actual amount of an mRNA or protein present. Such assays are coupled with processes or systems to store and process information and to help quantify levels, signals, etc. and to digitize the information for use in comparing levels. 25 The term “otherwise identical sample”, as used herein, refers to a sample similar to a first sample, that is, it is obtained in the same manner from the same subject from the same tissue or fluid, or it refers a similar sample obtained from a different subject. The term “otherwise identical sample from an unaffected subject” refers to a sample obtained from a subject not known to have the disease or disorder being examined. The sample may of course be a standard sample. By analogy, the term 30 “otherwise identical” can also be used regarding regions or tissues in a subject or in an unaffected subject. As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, 35 but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through - 25 - Attorney Docket No.: 3436 / 3 PCT a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques. The term “pharmaceutical composition” refers to a composition comprising at least one active 5 ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan. “Pharmaceutically acceptable” means physiologically tolerable, for either human or veterinary 10 application. Similarly, “pharmaceutical compositions” include formulations for human and veterinary use. As used herein, the term “pharmaceutically acceptable carrier” means a chemical composition with which an appropriate compound or derivative can be combined and which, following the combination, can be used to administer the appropriate compound to a subject. 15 As used herein, the term “physiologically acceptable” ester or salt means an ester or salt form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered. “Plurality” means at least two. As used herein, the term “mass spectrometry” (MS) refers to a technique for the identification 20 and / or quantitation of molecules in a sample. MS includes ionizing the molecules in a sample, forming charged molecules; separating the charged molecules according to their mass-to-charge ratio; and detecting the charged molecules. MS allows for both the qualitative and quantitative detection of molecules in a sample. The molecules can be ionized and detected by any suitable means known to one of skill in the art. Some examples of mass spectrometry are “tandem mass spectrometry” or “MS / MS,” 25 which are the techniques wherein multiple rounds of mass spectrometry occur, either simultaneously using more than one mass analyzer or sequentially using a single mass analyzer. The term “mass spectrometry” can refer to the application of mass spectrometry to protein analysis. In some embodiments, electrospray ionization (ESI) and matrix-assisted laser desorption / ionization (MALDI) can be used in this context. In some embodiments, intact protein molecules can be ionized by the above 30 techniques, and then introduced to a mass analyzer. Alternatively, protein molecules can be broken down into smaller peptides, for example, by enzymatic digestion by a protease, such as trypsin. Subsequently, the peptides are introduced into the mass spectrometer and identified by peptide mass fingerprinting or tandem mass spectrometry. As used herein, the term “mass spectrometer” is used to refer an apparatus for performing mass 35 spectrometry that includes a component for ionizing molecules and detecting charged molecules. Various types of mass spectrometers can be employed in the methods of the presently disclosed subject - 26 - Attorney Docket No.: 3436 / 3 PCT matter. For example, whole protein mass spectroscopy analysis can be conducted using time-of-flight (TOF) or Fourier transform ion cyclotron resonance (FT-ICR) instruments. For peptide mass analysis, MALDI time-of-flight instruments can be employed, as they permit the acquisition of peptide mass fingerprints (PMFs) at high pace. Multiple stage quadrupole-time-of-flight and the quadrupole ion trap 5 instruments can also be used. The terms “high throughput protein identification,” “proteomics” and other related terms are used herein to refer to the processes of identification of a large number or (in some cases, all) proteins in a certain protein complement. Post-translational protein modifications and quantitative information can also be assessed by such methods. One example of “high throughput protein identification” is a gel- 10 based process that includes the pre-fractionation and purification of proteins by one-dimensional protein gel electrophoresis. The gel can then be fractionated into several molecular weight fractions to reduce sample complexity, and proteins can be in-gel digested with trypsin. The tryptic peptides are extracted from the gel, further fractionated by liquid chromatography, and analyzed by mass spectrometry. In another approach, a sample can be fractionated without using the gels, for example, by protein 15 extraction followed by liquid chromatography. The proteins can then be digested in-solution, and the proteolytic fragments further fractionated by liquid chromatography and analyzed by mass spectrometry. As used herein, the term “Western blot,” which can be also referred to as “immunoblot”, and related terms refer to an analytical technique used to detect specific proteins in a sample. The technique 20 uses gel electrophoresis to separate the proteins, which are then transferred from the gel to a membrane (typically nitrocellulose or PVDF) and stained, in membrane, with antibodies specific to the target protein. The expression “stable isotope labeling by amino acids in cell culture” (SILAC) is used herein to refer to an approach for incorporation of a label into proteins for mass spectrometry (MS)-based 25 quantitative proteomics. SILAC comprises metabolic incorporation of a given “light” or “heavy” form of the amino acid into the proteins. For example, SILAC comprises the incorporation of amino acids with substituted stable isotopic nuclei (e.g. deuterium,13C,15N). In an illustrative SILAC experiment, two cell populations are grown in culture media that are identical, except that one of them contains a “light” and the other a “heavy” form of a particular amino acid (for example,12C and13C labeled L- 30 lysine, respectively). When the labeled analog of an amino acid is supplied to cells in culture instead of the natural amino acid, it is incorporated into all newly synthesized proteins. After a number of cell divisions, each instance of the amino acid is replaced by its isotope-labeled analog. Since there is little chemical difference between the labeled amino acid and the natural amino acid isotopes, the cells behave substantially similar to the control cell population grown in the presence of a normal amino acid. 35 The term “prevent” as used herein means to stop something from happening, or taking advance measures against something possible or probable from happening. In the context of medicine, - 27 - Attorney Docket No.: 3436 / 3 PCT “prevention” generally refers to action taken to decrease the chance of getting a disease or condition. It is noted that “prevention” need not be absolute, and thus can occur as a matter of degree. A “preventive” or “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs, or exhibits only early signs, of a condition, disease, or disorder. A prophylactic or 5 preventative treatment is administered for the purpose of decreasing the risk of developing pathology associated with developing the condition, disease, or disorder. “Polypeptide” refers to a polymer composed of amino acid residues, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof linked via peptide bonds, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof. 10 “Synthetic peptides or polypeptides” refers to non-naturally occurring peptides or polypeptides. Synthetic peptides or polypeptides can be synthesized, for example, using an automated polypeptide synthesizer. Various solid phase peptide synthesis methods are known to those of skill in the art. The term “protein” typically refers to large polypeptides (e.g., greater than 50 amino acid residues). Conventional notation is used herein to portray polypeptide sequences: the left-hand end of 15 a polypeptide sequence is the amino-terminus; the right-hand end of a polypeptide sequence is the carboxyl-terminus. As used herein, the term “peptide” refers to a smaller polypeptide, e.g., having 2 to about 50 amino acid residues (e.g., about 5 to 50 amino acid or 10 to 50 amino acid residues). The term “amino acid residue” refers to a moiety resulting from the incorporation of an amino 20 acid into a polypeptide, e.g., a moiety having the structure -NH-CH(R)-C(=O)-, where R corresponds to the side chain of the amino acid from which the residue originates. The term “proteome” refers to the entire set of proteins expressed by a genome, cell, tissue, or organism at a particular time and / or under particular conditions. As used herein, the term “purified” and like terms relate to an enrichment of a molecule or 25 compound relative to other components normally associated with the molecule or compound in a native environment. The term “purified” does not necessarily indicate that complete purity of the particular molecule has been achieved during the process. A “highly purified” compound as used herein refers to a compound that is in some embodiments greater than 90% pure, that is in some embodiments greater than 95% pure, and that is in some 30 embodiments greater than 98% pure. As used herein, the term “mammal” refers to any member of the class Mammalia, including, without limitation, humans, and nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats, and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs, and the like. The term 35 does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included within the scope of this term. - 28 - Attorney Docket No.: 3436 / 3 PCT The term “subject” as used herein refers to a member of species for which treatment and / or prevention of a disease or disorder using the compositions and methods of the presently disclosed subject matter might be desirable. Accordingly, the term “subject” is intended to encompass in some embodiments any member of the Kingdom Animalia including, but not limited to the phylum Chordata 5 (e.g., members of Classes Osteichythyes (bony fish), Amphibia (amphibians), Reptilia (reptiles), Aves (birds), and Mammalia (mammals), and all Orders and Families encompassed therein. The compositions and methods of the presently disclosed subject matter are particularly useful for warm-blooded vertebrates. Thus, in some embodiments the presently disclosed subject matter concerns mammals and birds. More particularly provided are compositions and methods derived from 10 and / or for use in mammals such as humans and other primates, as well as those mammals of importance due to being endangered (such as Siberian tigers), of economic importance (animals raised on farms for consumption by humans) and / or social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), rodents (such as mice, 15 rats, and rabbits), marsupials, and horses. Also provided is the use of the disclosed methods and compositions on birds, including those kinds of birds that are endangered, kept in zoos, as well as fowl, and more particularly domesticated fowl, e.g., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economic importance to humans. Thus, also provided is the use of the disclosed methods and compositions on livestock, including but not limited to domesticated swine 20 (pigs and hogs), ruminants, horses, poultry, and the like. A “sample”, as used herein, refers in some embodiments to a biological sample from a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine. A sample can also be any other source of material obtained from a subject which contains proteins, cells, tissues, or fluid of interest. A sample can also be obtained from cell or 25 tissue culture. The term “standard”, as used herein, refers to something used for comparison. For example, it can be a known standard agent or compound which is administered and used for comparing results when administering a test compound, or it can be a standard parameter or function which is measured to obtain a control value when measuring an effect of an agent or compound on a parameter or function. Standard 30 can also refer to an “internal standard”, such as an agent or compound which is added at known amounts to a sample and is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured. Internal standards are often a purified marker of interest which has been labeled, such as with a radioactive isotope, allowing it to be distinguished from an endogenous marker. 35 A “subject” of analysis, diagnosis, or treatment is an animal. Such animals include mammals, in some embodiments, humans. - 29 - Attorney Docket No.: 3436 / 3 PCT As used herein, a “subject in need thereof” is a patient, animal, mammal, or human, who will benefit from the method of this presently disclosed subject matter. The term “substantially pure” describes a compound, e.g., a protein or polypeptide, which has been separated from components which naturally accompany it. Typically, a compound is substantially 5 pure when in some embodiments at least 10%, in some embodiments at least 20%, in some embodiments at least 50%, in some embodiments at least 60%, in some embodiments at least 75%, in some embodiments at least 90%, and in some embodiments at least 99% of the total material (by volume, by wet or dry weight, or by mole percent or mole fraction) in a sample is the compound of interest. Purity can be measured by any appropriate method, e.g., in the case of polypeptides by column 10 chromatography, gel electrophoresis, or HPLC analysis. A compound, e.g., a protein, is also substantially purified when it is essentially free of naturally associated components or when it is separated from the native contaminants which accompany it in its natural state. The term “symptom”, as used herein, refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the patient and indicative of disease. In 15 contrast, a “sign” is objective evidence of disease. For example, a bloody nose is a sign. It is evident to the patient, doctor, nurse, and other observers. A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs. A “therapeutically effective amount” of a compound is that amount of compound which is 20 sufficient to provide a beneficial effect to the subject to which the compound is administered. As used herein, the phrase “therapeutic agent” refers to an agent that is used to, for example, treat, inhibit, prevent, mitigate the effects of, reduce the severity of, reduce the likelihood of developing, slow the progression of, and / or cure, a disease or disorder. The terms “treatment” and “treating” as used herein refer to both therapeutic treatment and 25 prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition, prevent the pathologic condition, pursue or obtain beneficial results, and / or lower the chances of the individual developing a condition, disease, or disorder, even if the treatment is ultimately unsuccessful. Those in need of treatment include those already with the condition as well as those prone to have or predisposed to having a condition, disease, or disorder, or those in 30 whom the condition is to be prevented. All genes, gene names, and gene products disclosed herein are intended to correspond to homologs and / or orthologs from any species for which the compositions and methods disclosed herein are applicable. Thus, the terms include, but are not limited to genes and gene products from humans and mice. It is understood that when a gene or gene product from a particular species is disclosed, this 35 disclosure is intended to be exemplary only, and is not to be interpreted as a limitation unless the context in which it appears clearly indicates. - 30 - Attorney Docket No.: 3436 / 3 PCT As used herein, the term “ABAD” refers to the abhydrolase domain containing 10, depalmitoylase gene and its transcription and translation products. ABAD is also known as hydroxysteroid 17-beta dehydrogenase 10 (HSD17B10). Exemplary human ABAD nucleic acid and amino acid sequences are presented in Accession Nos. NM_004493.3 and NP_004484.1 of the 5 GENBANK® biosequence database. As used herein, the term “ABHD10” refers to the 3-hydroxyacyl-CoA dehydrogenase type-2 gene and its transcription and translation products. Exemplary human ABHD10 nucleic acid and amino acid sequences are presented in Accession Nos. NM_018394.4 and NP_060864.1 of the GENBANK® biosequence database. 10 As used herein, the term “GSTP1” refers to the glutathione S-transferase pi 1 gene and its transcription and translation products. Exemplary human GSTP1 nucleic acid and amino acid sequences are presented in Accession Nos. NM_000852.4 and NP_000843.1 of the GENBANK® biosequence database. As used herein, the term “GNPNAT1” refers to the glucosamine-phosphate N-acetyltransferase 15 1 gene and its transcription and translation products. Exemplary human GNPNAT1 nucleic acid and amino acid sequences are presented in Accession Nos. NM_198066.4 and NP_932332.1 of the GENBANK® biosequence database. As used herein, the term “PARP2” refers to the poly(ADP-ribose) polymerase 2 gene and its transcription and translation products. Exemplary human PARP2 nucleic acid and amino acid sequences 20 are presented in Accession Nos. NM_005484.4 and NP_005475.2 of the GENBANK® biosequence database. As used herein, the term “ACAT2” refers to the acetyl-CoA acetyltransferase 2 gene and its transcription and translation products. Exemplary human ACAT2 nucleic acid and amino acid sequences are presented in Accession Nos. NM_005891.3 and NP_005882.2 of the GENBANK® 25 biosequence database. As used herein, the term “GNAS” refers to the GNAS complex locus and its transcription and translation products. Exemplary human GNAS nucleic acid and amino acid sequences are presented in Accession Nos. NM_000516.7 and NP_000507.1 of the GENBANK® biosequence database. As used herein the term “alkyl” refers to C1-20inclusive, linear (i.e., “straight-chain”), branched, 30 or cyclic, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. In some 35 embodiments, the alkyl group is “lower alkyl.” “Lower alkyl” refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-8alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. In some embodiments, the - 31 - Attorney Docket No.: 3436 / 3 PCT alkyl is “higher alkyl.” “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, “alkyl” refers, in particular, to C1-8straight-chain alkyls. In other embodiments, “alkyl” refers, in particular, to C1-8branched-chain alkyls. 5 Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term “alkyl group substituent” includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, 10 wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl. Thus, as used herein, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, 15 hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto. The term “aryl” is used herein to refer to an aromatic moiety that can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group, such as, but not limited to, a methylene or ethylene moiety. The common linking group also can be a carbonyl, as in benzophenone, or oxygen, as in diphenylether, or nitrogen, as in diphenylamine. The 20 term “aryl” specifically encompasses heterocyclic aromatic compounds. The aromatic ring(s) can comprise phenyl, naphthyl, biphenyl, diphenylether, diphenylamine and benzophenone, among others. In particular embodiments, the term “aryl” means a cyclic aromatic comprising about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5- and 6-membered hydrocarbon and heterocyclic aromatic rings. 25 The aryl group can be optionally substituted (a “substituted aryl”) with one or more aryl group substituents, which can be the same or different, wherein “aryl group substituent” includes alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, carbonyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and -NR’R’’, 30 wherein R’ and R’’ can each be independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl. Thus, as used herein, the term “substituted aryl” includes aryl groups, as defined herein, in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, 35 hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto. - 32 - Attorney Docket No.: 3436 / 3 PCT Specific examples of aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, and the like. The term “heteroaryl” refers to aryl groups wherein at least one atom of the backbone of the 5 aromatic ring or rings is an atom other than carbon. Thus, heteroaryl groups have one or more non- carbon atoms selected from the group including, but not limited to, nitrogen, oxygen, and sulfur. As used herein, the term “acyl” refers to an organic carboxylic acid group wherein the -OH of the carboxyl group has been replaced with another substituent, i.e., as represented by -C(=O)R, wherein R is an alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl or substituted aryl group as defined 10 herein). As such, the term “acyl” specifically includes arylacyl groups, such as an acetylfuran and a phenacyl group. Specific examples of acyl groups include acetyl and benzoyl. “Cyclic” and “cycloalkyl” refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group can be optionally partially unsaturated. The cycloalkyl group also can be optionally substituted with an alkyl 15 group substituent as defined herein, oxo, and / or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, 20 camphane, and noradamantyl. The terms “heterocycle”, “heterocyclyl” “heterocycloalkyl” or “heterocyclic” refer to cycloalkyl groups (i.e., non-aromatic, cyclic groups as described hereinabove) wherein one or more of the backbone carbon atoms of a cyclic ring is replaced by a heteroatom (e.g., nitrogen, sulfur, or oxygen). Examples of heterocycles include, but are not limited to, tetrahydrofuran, tetrahydropyran, 25 morpholine, dioxane, piperidine, piperazine, and pyrrolidine. Additional examples of heterocycles include, for example, the cyclic forms of sugars, such as ribose, glucose, galactose, and the like. “Alkylene” refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group also can be optionally 30 unsaturated and / or substituted with one or more “alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-C6H10-); -CH=CH—CH=CH-; -CH=CH-CH2-; -(CH2)q-N(R)- 35 (CH2)r-, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl - 33 - Attorney Docket No.: 3436 / 3 PCT (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons. “Alkoxyl” or “alkoxy” refers to an alkyl-O- group wherein alkyl is as previously described. The term “alkoxyl” as used herein can refer to, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, 5 butoxyl, t-butoxyl, and pentoxyl. The term “oxyalkyl” can be used interchangably with “alkoxyl”. The terms “aryloxy” and “aryloxyl” refer to an aryl-O-group, wherein aryl is as previously described. The term “aryloxy as used herein can refer to, for example, phenoxy, p-chlorophenoxy, p- fluorophenoxy, p-methylphenoxy, p-methoxyphenoxy, and the like. “Aralkyl” refers to an aryl-alkyl- group wherein aryl and alkyl are as previously described and 10 include substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl. In some embodiments, the aromatic portion of the aralkyl group can be substituted by one or more aryl group substituents and / or the alkyl portion of the aralkyl group can be substituted by one or more alkyl group substituents and the aralkyl group can be a “substituted aralkyl” group. The term “amino” refers to the -NR’R” group, wherein R’ and R” are each independently 15 selected from the group including H and substituted and unsubstituted alkyl, cycloalkyl, heterocycle, aralkyl, aryl, and heteroaryl. In some embodiments, the amino group is -NH2. The terms “alkylamino” and “aminoalkyl” refer to a -NHR group where R is alkyl or substituted alkyl. The term “arylamino” refers to a -NHR group where R is aryl or substituted aryl. The term “carbonyl” refers to the -(C=O)- or a double bonded oxygen substituent attached to a 20 carbon atom of a previously named parent group. The terms “carboxylate” and “carboxylic acid” can refer to the groups -C(=O)-O- and -C(=O)- OH, respectively. In some embodiments, “carboxylate” can refer to either the -C(=O)-O- or -C(=O)-OH group. In some embodiments, the term “carboxyl” can also be used to refer to a carboxylate or carboxylic acid group. 25 The terms “sulfonyl” as used herein refers to the -S(=O)2- or -S(=O)2R group, wherein R is alkyl, substituted alkyl, cycloalkyl, heterocycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. The term “sulfonamide” refers to the -S(=O)2-N(R)2group, wherein each R is independently selected from H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl, or 30 wherein the two R together can form a ring with the nitrogen atom (e.g., wherein the two R together are an alkylene group, such as a butylene or pentylene group). The term “sulfonate” as used herein refers to a -S(=O)2-O-R group, wherein R is selected from alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl. The terms “halo”, “halide”, or “halogen” as used herein refer to fluoro, chloro, bromo, and iodo 35 groups. - 34 - Attorney Docket No.: 3436 / 3 PCT The term “perhaloalkyl” refers to an alkyl group wherein all of the hydrogen atoms are replaced by halo. Thus, for example, perhaloalkyl can refer to a “perfluroalkyl” group wherein all of the hydrogen atoms of the alkyl group are replaced by fluoro. Perhaloalkyl groups include, but are not limited to, - CF3. 5 The terms “hydroxyl” and “hydroxy” refer to the -OH group. The term “oxo” refers to a compound described previously herein wherein a carbon atom is replaced by an oxygen atom. The term “thio” refers to the -S- or -SH group. The terms “alkylthio” and “thioalkyl” refer to a -SR group where R is alkyl or substituted alkyl. 10 The term “arylthiol” refers to a -SR group where R is aryl or substituted aryl. The term “cyano” refers to the -CN group. The term “nitro” refers to the -NO2group. A line crossed by a wavy line, e.g., in the structure: 15 indicates the site where the indicated substituent or structure can bond to another group. II. Sulfonyl-purine (SuPUR) Covalent probes and ligands can serve as useful tools for the global investigation of protein function. For example, activity-based protein profiling (ABPP) utilizes active-site directed chemical probes to measure the functional state of large numbers of enzymes in native biological systems (e.g., 20 cells or tissues). Activity-based probes can comprise a reactive group for targeting a specific enzyme class and a reporter tag for detection e.g., by in-gel fluorescence scanning or by avidin-enrichment coupled with liquid chromatography mass spectrometry (LCMS), respectively. Tuning the reactivity of sulfur electrophiles can be important for developing biorthogonal chemical probe discovery. To date, the activation of sulfur electrophiles for protein modification has 25 been related mainly to stabilizing a fluoride or a triazole leaving group (LG) in covalent reactions of sulfonyl-fluorides in sulfonyl-fluoride exchange (SuFEx) probes and ligands and in sulfonyl-triazoles in sulfonyl-triazole exchange (SuTEx) probes and ligands. General structures of SuFEx probe and SuTEx compounds are shown in Figure 1A. The presently disclosed subject matter relates to the use of sulfonyl-purine and sulfonyl-purine analog (e.g., sulfonyl-xanthine or sulfonyl-hypoxanthine) 30 compounds as sulfur electrophiles as part of an approach referred to herein as “sulfonyl-purine (SuPUR)” or “SuPUR” chemistry. The structure of a generic SuPUR compound is shown on the right side of Figure 1A. The structure of an exemplary SuPUR probe compound is shown in Figure 1B, while a workflow of the use of the SuPUR probe in proteomic studies is shown in Figure 1D. The SuPUR - 35 - Attorney Docket No.: 3436 / 3 PCT probe compound includes a terminal alkyne moiety that can act as a reporter tag, for instance, upon Click reaction with a desthiobiotin azide. The structure of an exemplary SuPUR ligand compound is shown in Figure 1C. As described herein, the SuPUR approach demonstrates that purine and purine analogs can be 5 effective leaving groups for activating nucleophilic substitution reactions (e.g., of tyrosine and lysine sites of peptides and proteins; see Figures 1E and 1F) and that SuPUR compounds can be used as covalent ligands that form covalent conjugates with nucleophilic groups in peptides and proteins. Proteomic studies using SuPUR compounds identified noncatalytic tyrosine and lysine residues that can be liganded by exemplary SuPUR ligands with site specificity and potency to disrupt protein function. 10 More particularly, as described hereinbelow, for example, a series of covalent SuPUR ligands were prepared and selective covalent labeling of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD) and alpha / beta (^ / ^)-hydrolase domain 10 (ABHD10) was studied. Covalent modification of ABAD and ABHD10 with these compounds can inhibit the function of these enzymes, which are known to be closely related to mitochondrial metabolism and S-depalmitoylase. These compounds demonstrate the 15 broad utility of SuPUR chemistry for targeting functional pockets on proteins. For example, in some embodiments, the presently disclosed subject matter provides a family of covalent ligands targeting an ABAD tyrosine (Tyr) residue to achieve the inhibition of ABAD, thereby advancing basic research in Alzheimer’s disease (AD) and / or for facilitating development of therapeutic agents (e.g., small molecule agents) for treating AD. In some embodiments, the SuPUR ligand 20 covalently modifies (e.g., selectively and covalently modifies) tyrosine-168 (Y168) of ABAD. In some embodiments, the presently disclosed subject matter provides a family of covalent ligands for targeting an ABHD10 tyrosine (Try) residue to provide an ABHD10 inhibitor with improved selectivity compared to inhibitors that target serine residues. In some embodiments, the SuPUR ligand covalent modifies (e.g., selectively and covalently modifies) tyrosine-87 (Y87) and / or tyrosine-215 (Y215) of 25 ABHD10. II.A. Compositions In some embodiments, the presently disclosed subject matter provides a compound (referred to herein as a SuPUR compound) comprising a sulfonyl-purine or sulfonyl-purine analog. The sulfonyl- purine analog can comprise, for example, a fused imidazole-based moiety, such as, a hypoxanthine, a 30 xanthine, an imidazopyridine, or a benzimidazole moiety. The purine or purine analog can be substituted or unsubstituted. In some embodiments, the presently disclosed subject matter provides a compound having a structure of Formula (I): - 36 - Attorney Docket No.: 3436 / 3 PCT (Formula I), wherein: each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group 5 consisting of H, O, F, Cl, Br,-NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl (e.g., C1-C6 alkyl), aralkyl (e.g., benzyl), aryl (e.g., phenyl), -C(=O)H, -C(=O)- alkyl, and a nitrogen-protecting group; X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R; and R is selected from -S(=O)2-R1and -CH2-S(=O)2-R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, 10 substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, X1and X2are independently selected from the group consisting of H, O, -NH2, -NHX5, and -N(X5)2. In some embodiments, R is -S(=O)-R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, 15 heteroaryl, and substituted heteroaryl, optionally wherein R1is selected from phenyl and substituted phenyl; or a pharmaceutically acceptable salt thereof. Thus, in some embodiments, the compound of Formula (I) has a structure of Formula (I’): (Formula I’), each represents a single or double bond; subject to the proviso that three represent a 20 double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group consisting of H, O, F, Cl, Br,-NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; -S(=O)2-R1is covalently attached to one of nitrogen atom 1 and nitrogen atom 3; and R1is selected from the group consisting of 25 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, X1and X2are independently selected from the group consisting of H, O, -NH2, -NHX5, and -N(X5)2. In some embodiments, Z and Y are each selected from N and NH. - 37 - Attorney Docket No.: 3436 / 3 PCT In some embodiments, X1is O, Z is NH, X2is H, and Y is N. Thus, in some embodiments, the compound of Formula (I) has a structure comprising Formula (Ia): Formula (Ia), where each represents a single or double bond; subject to the proviso that one represents 5 a double bond and one represents a single bond; and wherein X3and X4are as defined for Formula (I). In some embodiments, one of X3and X4is H and one of X3and X4is -S(=O)2-R1. In some embodiments, X4is -S(=O)2-R1. In some embodiments, R1is phenyl or substituted phenyl. In some embodiments, R1is -C6H4-C(=O)-NH-CH2-C^CH. In some embodiments, the compound of Formula (Ia) is: 10 (referred to herein as “ZH-1-142”). In some embodiments, both X1and X2are O and both of Y and Z are NH. Thus, in some embodiments, the compound of Formula (I) has a structure of Formula (Ib): where each represents a single or double bond; subject to the proviso that one represents 15 a double bond and one represents a single bond; wherein X3and X4are as defined for Formula (I). In some embodiments, one of X3and X4is H and one of X3and X4is -S(=O)2-R1. In some embodiments, X4is -S(=O)2-R1. In some embodiments, R1is phenyl or substituted phenyl. In some embodiments, R1is -C6H4-C(=O)-NH-CH2-C^CH. In some embodiments, the compound of Formula (Ib) is: - 38 - Attorney Docket No.: 3436 / 3 PCT (referred to herein as “ZH-1-143”). In some embodiments, neither X1nor X2is O. In some embodiments, the compound of Formula (I) has a structure of Formula (Ic): 5 where each represents a single or double bond; subject to the proviso that one represents a double bond and one represents a single bond; Z is selected from CH and N; Y is selected from CH and N; X1and X2are independently selected from the group consisting of H, F, Cl, Br,-NH2, - NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, - C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; X3and X4are selected from H and R, wherein10 one of X3and X4is H and one of X3and X4is R; and R is selected from -S(=O)2-R1and -CH2-S(=O)2- R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, X1and X2are independently selected from the group consisting of H, O, -NH2, -NHX5, and -N(X5)2. In some embodiments, R is -S(=O)2-R1. 15 In some embodiments, Z and Y are each N. In some embodiments, the compound of Formula (I) has a structure of Formula (II): wherein: Z is CH or N;Y is CH or N; X1and X2are independently selected from the group consisting of H, F, Cl, Br, -NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of 20 alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alky l, and a nitrogen-protecting group; and R1is selected from - 39 - Attorney Docket No.: 3436 / 3 PCT the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, one of Z and Y is CH. In some embodiments, both Z and Y are CH. In 5 some embodiments, X1and X2are each H. In some embodiments, the compound has a structure selected from: ZH-2-035 ZH-2-036. In some embodiments, Z and Y are each N. In some embodiments, the compound of Formula 10 (II) has a structure of Formula (II’): (Formula II’), wherein: X1and X2are independently selected from the group consisting of -H, -NH2, -NHX5, and - N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)-H, -C(=O)- alkyl, and a nitrogen-protecting group; and R1is selected from the group consisting of alkyl, substituted 15 alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof. In some embodiments, X1and / or X2is / are H. In some embodiments, R1is C1-C6 alkyl or C1-C6 substituted alkyl. In some embodiments, R1is perhaloalkyl-substituted (e.g., -CF3-substituted) C1-C6 alkyl. In some embodiments, R1is alkoxy- substituted alkyl. In some embodiments, R1is a branched C1-C6 alkyl (e.g., isopropyl, sec-butyl (i.e., 20 butan-2-yl) or isobutyl (i.e., 2-methylpropyl). In some embodiments, R1is C3-C6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the compound has a structure selected from: - 40 - Attorney Docket No.: 3436 / 3 PCT ZH-1-059 ZH-1-060 ZH-1-063 ZH-1-089 In some embodiments, R1is phenyl or substituted phenyl. In some embodiments, the compound of Formula (II) has a structure of Formula (III): 5 wherein Z is CH or N; Y is CH or N; X1and X2are independently selected from the group consisting of H, F, Cl, Br, -NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)-H, -C(=O)-alkyl, and a nitrogen-protecting group; R2, R3, R4, R5, and R6are independently selected from the group consisting of H, cyano, halo, alkyl, perhaloalkyl (e.g.,10 perfluoroalkyl), alkoxy, perhaloalkoxy (e.g., perfluoroalkoxy), carboxyl, formyl (i.e., -C(=O)-H), - C(=O)-R7, -NH-C(=O)-R7, and -C(=O)-N(R8)2; R7is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl; and each R8is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, and substituted aralkyl; or where two R8groups together with the nitrogen to which 15 they are attached form a substituted or unsubstituted nitrogen-containing heterocyclic ring; or a pharmaceutically acceptable salt thereof. In some embodiments, Z and Y are each N. In some embodiments, the compound of Formula (III) has a structure of Formula (III’): - 41 - Attorney Docket No.: 3436 / 3 PCT Formula (III’), wherein X1,X2, R2, R3, R4, R5, and R6are defined as described above for Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, for the compound of Formula (III) or (III’), R2, R3, R4, R5, and R6are 5 independently selected from the group consisting of H, cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, trifluoroalkoxy, methoxy, carboxyl, formyl, acetyl (-C(=O)-CH3), -NH-C(=O)-alkyl, - C(=O)-NHR8, and , where R8is selected from terminal alkyne-substituted alkyl (e.g., -CH2-C^CH), cycloalkyl, cycloalkyl- 10 substituted alkyl, aralkyl, and aryl; and R9is aralkyl. In some embodiments, one or both of R2and R6are selected from the group consisting of fluoro, chloro, bromo, methyl, perfluoromethyl, methoxy, and perfluoromethoxy. In some embodiments, R4is cyano. In some embodiments, in the compound of Formula (I), R is selected from the group consisting 15 of: , - 42 - Attorney Docket No.: 3436 / 3 PCT - 43 - Attorney Docket No.: 3436 / 3 PCT 5 In some embodiments, Z and Y are each N, and X1and X2are each H. In some embodiments, the presently disclosed compounds are provided in the form of pharmaceutically acceptable salts or solvates. II.B. Pharmaceutical Compositions and Administration 10 The presently disclosed subject matter also relates, in some embodiments, to pharmaceutical compositions comprising, consisting essentially of, or consisting of one or more SuPUR compounds of - 44 - Attorney Docket No.: 3436 / 3 PCT the presently disclosed subject matter and a pharmaceutically acceptable carrier, diluent, and / or excipient. Pharmaceutical compositions comprising the present compounds are administered to a subject in need thereof by any number of routes including, but not limited to, topical, oral, intravenous, 5 intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means. As such, in some embodiments the presently disclosed compositions are administered by injecting the composition subcutaneously, intraperitoneally, into adipose tissue, and / or intramuscularly into the subject. In accordance with some embodiments, a method for treating a subject in need of such treatment 10 is provided. The method comprises administering a pharmaceutical composition comprising at least one compound of the presently disclosed subject matter to a subject in need thereof. Compounds identified by the methods of the presently disclosed subject matter can be administered with known compounds or other medications as well. The pharmaceutical compositions useful for practicing the presently disclosed subject matter 15 may be administered to deliver a dose of between 1 ng / kg / day and 100 mg / kg / day. The presently disclosed subject matter encompasses the preparation and use of pharmaceutical compositions comprising a compound useful for treatment of the diseases and disorders disclosed herein as an active ingredient. Such a pharmaceutical composition may consist of the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the 20 active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these. The active ingredient may be present in the pharmaceutical composition in the form of a physiologically acceptable ester or salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art. As used herein, the term “physiologically acceptable” ester or salt means an ester or salt form 25 of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subject to which the composition is to be administered. The compositions of the presently disclosed subject matter may comprise at least one active peptide, one or more acceptable carriers, and optionally other peptides or therapeutic agents. For in vivo applications, the compositions of the presently disclosed subject matter may 30 comprise a pharmaceutically acceptable salt. Suitable acids which are capable of forming such salts with the compounds of the presently disclosed subject matter include inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, phosphoric acid and the like; and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, anthranilic acid, cinnamic acid, naphthalene sulfonic acid, sulfanilic acid and the like. 35 Pharmaceutically acceptable carriers include physiologically tolerable or acceptable diluents, excipients, solvents, or adjuvants. The compositions are in some embodiments sterile and nonpyrogenic. - 45 - Attorney Docket No.: 3436 / 3 PCT Examples of suitable carriers include, but are not limited to, water, normal saline, dextrose, mannitol, lactose or other sugars, lecithin, albumin, sodium glutamate, cysteine hydrochloride, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, ethoxylated isosteraryl alcohols, polyoxyethylene sorbitol 5 and sorbitan esters, microcrystalline cellulose, aluminum methahydroxide, bentonite, kaolin, agar-agar and tragacanth, or mixtures of these substances, and the like. In some embodiments wherein a composition of the presently disclosed subject matter is desired to induce an immune response, the compositions of the presently disclosed subject matter can further comprise an adjuvant. In some embodiments, the at least one adjuvant is selected from the group 10 consisting of montanide ISA-51 (Seppic, Inc.), QS-21 (Aquila Pharmaceuticals, Inc.), tetanus helper peptides, GM-CSF, cyclophosamide, bacillus Calmette-Guerin (BCG), corynbacterium parvum, levamisole, azimezone, isoprinisone, dinitrochlorobenezene (DNCB), keyhole limpet hemocyanins (KLH), Freunds adjuvant (complete and incomplete), mineral gels, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, diphtheria toxin (DT). 15 The pharmaceutical compositions may also contain minor amounts of nontoxic auxiliary pharmaceutical substances or excipients and / or additives, such as wetting agents, emulsifying agents, pH buffering agents, antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, and the like). Suitable additives include, but are not limited to, physiologically biocompatible buffers (e.g., tromethamine hydrochloride), additions (e.g., 0.01 to 10 mole percent) of chelants (such 20 as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (as for example calcium DTPA or CaNaDTPA-bisamide), or, optionally, additions (e.g., 1 to 50 mole percent) of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate). If desired, absorption enhancing or delaying agents (such as liposomes, aluminum monostearate, or gelatin) may be used. The compositions can be prepared in conventional forms, either as liquid solutions 25 or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Pharmaceutical compositions according to the presently disclosed subject matter can be prepared in a manner fully within the skill of the art. The compositions of the presently disclosed subject matter, pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising these compounds can be so that the compounds 30 can have a physiological effect. Administration can occur enterally or parenterally; for example, orally, rectally, intracisternally, intravaginally, intraperitoneally, locally (e.g., with powders, ointments, or drops), or as a buccal or nasal spray or aerosol. Parenteral administration is preferred. Particularly preferred parenteral administration methods include intravascular administration (e.g., intravenous bolus injection, intravenous infusion, intra-arterial bolus injection, intra-arterial infusion, and catheter 35 instillation into the vasculature), peri- and intra-target tissue injection, subcutaneous injection or - 46 - Attorney Docket No.: 3436 / 3 PCT deposition including subcutaneous infusion, intramuscular injection, and direct application to the target area, for example by a catheter or other placement device. Where the administration is by injection or direct application, the injection or direct application can be in a single dose or in multiple doses. Where the administration of the compound is by infusion, 5 the infusion can be a single sustained dose over a prolonged period of time or multiple infusions. The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a 10 desired single- or multi-dose unit. It will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Subjects to which administration of the pharmaceutical compositions of the presently disclosed subject matter is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such 15 as cattle, pigs, horses, sheep, cats, and dogs, birds including commercially relevant birds such as chickens, ducks, geese, and turkeys. A pharmaceutical composition of the presently disclosed subject matter may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount 20 of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the presently disclosed subject matter will 25 vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient. In addition to the active ingredient, a pharmaceutical composition of the presently disclosed subject matter may further comprise one or more additional pharmaceutically active agents. Particularly 30 contemplated additional agents include anti-emetics and scavengers such as cyanide and cyanate scavengers. Controlled- or sustained-release formulations of a pharmaceutical composition of the presently disclosed subject matter may be made using conventional technology. As used herein, “additional ingredients” include, but are not limited to, one or more of the 35 following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring - 47 - Attorney Docket No.: 3436 / 3 PCT agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or 5 hydrophobic materials. Other “additional ingredients” which may be included in the pharmaceutical compositions of the presently disclosed subject matter are known in the art and described, for example in Gennaro, 1985; Gennaro, 1990; or Gennaro, 2003; each of which is incorporated herein by reference. Typically, dosages of the compound of the presently disclosed subject matter which may be administered to an animal, in some embodiments a human, range in amount from 1 μg to about 100 g 10 per kilogram of body weight of the animal. While the precise dosage administered will vary depending upon any number of factors, including but not limited to, the type of animal and type of disease state being treated, the age of the animal and the route of administration. In some embodiments, the dosage of the compound will vary from about 1 mg to about 10 g per kilogram of body weight of the animal. In another aspect, the dosage will vary from about 10 mg to about 1 g per kilogram of body weight of 15 the animal. The compound may be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, 20 such as, but not limited to, the type of cancer being diagnosed, the type and severity of the condition or disease being treated, the type and age of the animal, etc. Suitable preparations include injectables, either as liquid solutions or suspensions, however, solid forms suitable for solution in, suspension in, liquid prior to injection, may also be prepared. The preparation may also be emulsified, or the polypeptides encapsulated in liposomes. The active 25 ingredients are often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water saline, dextrose, glycerol, ethanol, or the like and combinations thereof. In addition, if desired, the vaccine preparation may also include minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and / or adjuvants. 30 The presently disclosed subject matter also includes a kit comprising the composition of the presently disclosed subject matter and an instructional material which describes administering the composition to a subject. In some embodiments, this kit comprises a (in some embodiments sterile) solvent suitable for dissolving or suspending the composition of the presently disclosed subject matter prior to administering the compound to the subject. 35 As used herein, an “instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of a composition of - 48 - Attorney Docket No.: 3436 / 3 PCT the presently disclosed subject matter in the kit for effecting alleviation of the various diseases or disorders recited herein. Optionally, or alternately, the instructional material may describe one or more methods of using the compositions for diagnostic or identification purposes or of alleviation the diseases or disorders in a cell or a tissue of a mammal. The instructional material of the kit of the presently 5 disclosed subject matter may, for example, be affixed to a container which contains a composition of the presently disclosed subject matter or be shipped together with a container which contains the composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient. The presently disclosed subject matter also related to methods for using the compositions of the 10 presently disclosed subject matter for various purposes. For example, in some embodiments the presently disclosed subject matter also relates to methods for treating and / or preventing diseases, disorders, and / or conditions associated with inflammation. II.C. Dosages An effective dose of a composition of the presently disclosed subject matter is administered to 15 a subject in need thereof. A “treatment effective amount” or a “therapeutic amount” is an amount of a therapeutic composition sufficient to produce a measurable response (e.g., a biologically or clinically relevant response in a subject being treated, such as but not limited to a reduction in scarring and / or fibrosis, particularly as compared to the same subject had the subject not received the composition). Actual dosage levels of active ingredients in the compositions of the presently disclosed subject matter 20 can be varied so as to administer an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular subject. The selected dosage level will depend upon the activity of the composition, the route of administration, combination with other drugs or treatments, the severity of the disease, disorder, and / or condition being treated, and the condition and prior medical history of the subject being treated. However, it is within the skill of the art to start doses of the 25 compositions of the presently disclosed subject matter at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. The potency of a composition can vary, and therefore a “treatment effective amount” can vary. However, using the methods described herein, one skilled in the art can readily assess the potency and efficacy of a composition of the presently disclosed subject matter and adjust the therapeutic regimen accordingly. 30 After review of the disclosure of the presently disclosed subject matter presented herein, one of ordinary skill in the art can tailor the dosages to an individual subject, taking into account the particular formulation, method of administration to be used with the composition, and particular disease, disorder, and / or condition treated. Further calculations of dose can consider subject height and weight, severity and stage of symptoms, and the presence of additional deleterious physical conditions. Such adjustments 35 or variations, as well as evaluation of when and how to make such adjustments or variations, are well known to those of ordinary skill in the art of medicine. - 49 - Attorney Docket No.: 3436 / 3 PCT II.D. Routes of Administration Suitable methods for administration of the compositions of the presently disclosed subject matter include, but are not limited to intravenous administration, oral delivery, and delivery directly to a target tissue or organ (e.g., a topical application and / or a site of injury such as but not limited to a 5 muscle injury). Exemplary routes of administration include parenteral, enteral, intravenous, intraarterial, intracardiac, intrapericardial, intraosseal, intracutaneous, subcutaneous, intradermal, subdermal, transdermal, intrathecal, intramuscular, intraperitoneal, intrasternal, parenchymatous, oral, sublingual, buccal, inhalational, and intranasal. The selection of a particular route of administration can be made based at least in part on the nature of the formulation and the ultimate target site where the 10 compositions of the presently disclosed subject matter are desired to act. In some embodiments, the method of administration encompasses features for regionalized delivery or accumulation of the compositions at the site in need of treatment. In some embodiments, the compositions are delivered directly into the site to be treated. By way of example and not limitation, in some embodiments a composition of the presently disclosed subject matter is administered to the subject via a route selected 15 from the group consisting of intraperitoneal, intramuscular, intravenous, and intranasal, or any combination thereof. The methods described herein use pharmaceutical compositions comprising the molecules described above, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and / or prophylactic ingredients. Such excipients include liquids such as 20 water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, cyclodextrins, modified cyclodextrins (i.e., sufobutyl ether cyclodextrins), etc. Suitable excipients for non-liquid formulations are also known to those of skill in the art. Pharmaceutically acceptable salts can be used in the compositions of the present invention and include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such 25 as acetates, propionates, malonates, benzoates, and the like. Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, may be present in such vehicles. A biological buffer can be virtually any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include 30 saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like. Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of a liquid, suspension, cream, ointment, lotion, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions can in some embodiments include one or more pharmaceutically acceptable carriers and, in addition, may include other 35 pharmaceutical agents, adjuvants, diluents, buffers, etc. - 50 - Attorney Docket No.: 3436 / 3 PCT III. Methods of Covalently Modifying Proteins Small molecules can serve as versatile tools for perturbing the functions of peptides and proteins in biological systems. Many human proteins currently lack selective chemical ligands; and there are several classes of proteins that are currently considered as undruggable. In some embodiments, 5 the presently disclosed SuPUR compounds can be used as covalent ligands to expand the landscape of proteins amenable to targeting by small molecules. In some instances, SuPUR compounds provide covalent ligands that combine features of recognition and reactivity, thereby providing for the selective targeting of sites on proteins of interest, including those that are difficult to address by reversible binding interactions alone and / or with other types of covalent ligands. 10 Scheme 1: SuPUR Reactions with Proteins with Reactive Tyrosine or Lysine Residues For example, Scheme 1 above shows the reaction of an exemplary SuPUR compound (e.g., an exemplary SuPUR ligand) with a protein having a reactive tyrosine (Y) or lysine (K). The SuPUR compound comprises a sulfur electrophile, i.e., a sulfonyl group directed attached to a nitrogen atom of 15 a purine moiety. The purine moiety acts as a leaving group (LG) in the reaction of the SuPUR compound with the nucleophilic phenol or amine moiety of the side chain of the tyrosine or lysine residue, resulting in a modified protein where a modified tyrosine or lysine residue is covalently attached to the sulfur atom from the SuPUR compound. The group -S(=O)2-R1from the SuPUR compound, which becomes covalently attached to the protein after the reaction, can be referred to herein 20 as an “adduct group” (or “AG”). AGs of SuPUR ligands can include a variety of optionally substituted alkyl, cycloalkyl (including heterocyclic), aryl (including heteroaryl), and aralkyl groups, while SuPUR “probes” can contain an AG group that comprises an alkyne group (e.g., a terminal alkyne group), a fluorophore moiety, another detectable moiety (e.g., an affinity label), or a combination thereof. In - 51 - Attorney Docket No.: 3436 / 3 PCT some embodiments, the alkyne group of an AG of a protein modified with a SuPUR probe can be contacted with an alkyne-reactive group (e.g., an azide) to attach a detectable group (e.g., a biotin) to the modified protein. In some embodiments, a SuPUR ligand of the presently disclosed subject matter can compete 5 with a SuPUR probe compound described herein for binding with a reactive amino acid residue, e.g., a reactive tyrosine and / or lysine residue. In some embodiments, the ligand molecule comprises an AG moiety that facilitates interaction of the compound with a particular amino acid residue of interest, e.g., a reactive tyrosine and / or lysine residue. In some cases, the ligand comprises an AG moiety that facilitates hydrophobic interaction, hydrogen bonding, or a combination thereof. In some embodiments, 10 the ligand can comprise an AG moiety that can increase or decrease steric hinderance at the electrophilic sulfonyl group, thereby modifying the reactivity of the ligand. The presently disclosed SuPUR ligands are typically non-naturally occurring and / or form non-naturally occurring adducts after reaction with a biological target, e.g., a protein or peptide. Exemplary SuPUR ligands include, for example, the compounds referred to herein as ZH-1-049-0, ZH-1-049-2, ZH-1-059, ZH-1-060, ZH-1-063, ZH-1-065, 15 ZH-1-069, ZH-1-075, ZH-1-089, ZH-2-017, ZH-2-018, ZH-2-019, ZH-2-020, ZH-2-022, ZH-2-023, ZH-2-024, ZH-2-025, ZH-2-026, ZH-2-027, ZH-2-029, ZH-2-035, ZH-2-036, ZH-2-039, ZH-2-053, ZH-2-058, ZH-2-067, ZH-2-069, ZH-2-071, ZH-2-073, ZH-2-077, ZH-2-079, ZH-2-085, ZH-2-087, ZH-2-093, ZH-2-095, ZH-2-097, ZH-2-099, ZH-2-101, ZH-2-103, ZH-2-105, ZH-2-115, and ZH-2- 055. Exemplary SuPUR probes include the compounds referred to herein as AHL-PuP-2, ZH-1-142, 20 and ZH-1-143. In some embodiments, the presently disclosed subject matter provides a method of covalently modifying a protein or peptide in a sample, wherein the method comprises contacting the sample with a SuPUR compound (e.g., a compound of Formula (I), (Ia), (Ib), (II), (II’), (III), or (III’) described hereinabove). In some embodiments, the contacting provides a covalent modified peptide or protein, 25 wherein said covalently modified peptide or protein comprises one or more covalently modified tyrosine or covalently modified lysine residues, wherein the covalently modified tyrosine or covalently modified lysine residues comprise a structure: - 52 - Attorney Docket No.: 3436 / 3 PCT wherein R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In some embodiments, R1is selected from phenyl and substituted phenyl. In some embodiments, the sample is a biological sample. In some embodiments, covalently 5 modifying the protein or peptide modulates a biological activity of the protein or peptide. In some embodiments, modifying the protein or peptide inhibits or activates a biological activity of the protein or peptide. For example, in some embodiments, the protein is an enzyme and covalently modifying the enzyme with the compound inhibits the enzyme. In some embodiments, modulating the activity of a protein comprises enhancing or reducing the ability of the protein to interact with other compounds,10 such as other proteins. Thus, in some embodiments, the modulation results in reducing the protein- protein interactions of the protein comprising the reactive amino acid. In some embodiments, modulating the activity of a protein comprising a comprises inhibiting, blocking (partially or substantially completely) or disrupting a protein-RNA interaction, a protein-DNA interaction, a protein- lipid interaction, and / or a protein-metabolite interaction of the protein. Thus, in accordance with some 15 embodiments of the presently disclosed subject matter, the presently disclosed ligands can serve as tools for the global investigation of protein function. In some embodiments, the protein or peptide is selected from ABAD, guanine nucleotide binding protein alpha stimulating activity polypeptide (GNAS), and ABHD10. In some embodiments, the protein is ABHD10 or another serine hydrolase. In some embodiments, the protein is ABAD. In some embodiments, the method comprises 20 contacting a sample comprising ABAD with a SuPUR compound as described herein. In some embodiments, the SuPUR compound is a compound of Formula (I). In some embodiments, Y and Z in the compound of Formula (I) are each selected from N and NH. In some embodiments, the SuPUR compound is a compound of Formula (Ia), (Ib), (II’), or (III’). In some embodiments, R in the SuPUR compound of Formula (I) is -S(=O)2-R1, wherein R1comprises a substituted phenyl group. In some25 embodiments, the substituted phenyl group comprises a halo, alkyl (e.g., methyl), perhaloalkyl (e.g., - CF3), perhaloalkoxy (e.g., -OCF3), or alkoxy (e.g., methoxy) substituent at one or both ortho positions. In some embodiments, the substituted phenyl group comprises a cyano substituent at the para position. In some embodiments, the SuPUR compound is selected from ZH-2-025, ZH-2-029, ZH-2-085, ZH-2- 093, and ZH-2-101. 30 In some embodiments, the SuPUR compound modifies ABAD at a non-catalytic tyrosine residue. In some embodiments, the non-catalytic tyrosine residue is tyrosine-168 (Y168). In some embodiments, the covalently modified ABAD exhibits lower enzymatic (or catalytic) activity compared to a corresponding unmodified ABAD (e.g., covalently modified human ABAD exhibits reduced enzymatic (or catalytic) activity compared to unmodified human ABAD under otherwise identical 35 conditions). In some embodiments, the covalently modified ABAD exhibits decreased binding for A^ compared to a corresponding unmodified ABAD. In some embodiments, the covalently modified - 53 - Attorney Docket No.: 3436 / 3 PCT ABAD exhibits a reduction in reactive oxygen species (ROS) induced by beta-amyloid (A^) compared to a corresponding unmodified ABAD. In some embodiments, the protein is ABHD10. In some embodiments, the method comprises contacting a sample comprising ABHD10 with a SuPUR compound as described herein. In some 5 embodiments, the SuPUR compound is a compound of Formula (I). In some embodiments, Y and Z in the compound of Formula (I) are each selected from N and NH. In some embodiments, the SuPUR compound is a compound of Formula (Ia), (Ib), (II’), or (III’). In some embodiments, R in the SuPUR compound of Formula (I) is -S(=O)2-R1, wherein R1comprises a substituted phenyl group. In some embodiments, the substituted phenyl group comprises a halo, alkyl (e.g., methyl), perhaloalkyl (e.g., - 10 CF3), or perhaloalkoxy (e.g., -OCF3) substituent at one or both ortho positions. In some embodiments, the SuPUR compound is selected from ZH-1-049-2, ZH-2-025, ZH-2-097, and ZH-2-103. In some embodiments, the SuPUR compound modifies ABHD10 at a non-catalytic tyrosine residue. In some embodiments, the non-catalytic tyrosine residue is tyrosine-215 (Y215). In some embodiments, the covalently modified ABHD10 exhibits lower enzymatic (or catalytic) activity 15 compared to a corresponding unmodified ABHD10 (e.g., covalently modified human ABHD10 exhibits reduced enzymatic (or catalytic) activity compared to unmodified human ABHD10 under otherwise identical conditions). In some embodiments, the sample comprises an isolated protein. In some embodiments, the sample comprises a cell lysate, a biological fluid (e.g., saliva, ascites, blood, urine, etc.) or a live cell. 20 In some embodiments, the sample comprising living cells comprises an organ, or a living organism (e.g., a subject, such as a human or other mammal). IV. Methods of Identifying Reactive Amino Acid Residues In some embodiments, the presently disclosed subject matter provides a method of identifying a reactive amino acid residue of a protein, the method comprising: providing a protein sample 25 comprising isolated proteins, living cells, or a cell lysate; (b) contacting the protein sample with a compound of Formula (I) (or a sub-formula thereof, e.g., Formula (II), (II’), (III), or (III’)) for a period of time sufficient for the compound to react with at least one reactive amino acid residue (e.g., a tyrosine or lysine residue) in a protein in the protein sample, thereby forming at least one modified reactive amino acid residue; and (c) analyzing proteins in the protein sample to identify at least one modified 30 reactive amino acid residue, thereby identifying at least one reactive amino acid residue of a protein; wherein the probe compound has a structure of Formula (I): - 54 - Attorney Docket No.: 3436 / 3 PCT wherein each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group consisting of H, O, F, Cl, Br,-NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group 5 consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; and X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R, and R is selected from -S(=O)2-R1, where R1is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl and substituted heteroaryl, wherein said substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl or substituted heteroaryl 10 comprises at least one substituent comprising a terminal alkyne moiety (e.g., a -CH2-C^CH moiety), a fluorophore, or a detectable tag; and wherein the at least one modified reactive amino acid residue comprises a structure -S(=O)2-R1. In some embodiments, Y and Z are each selected from N and NH. In some embodiments, the analyzing of step (c) further comprisies tagging the at least one modified reactive amino acid residue with a compound comprising a detectable labeling group, thereby 15 forming at least one tagged reactive amino acid residue comprising said detectable labeling group. In some embodiments, the detectable labeling group comprises biotin or a biotin derivative. In some embodiments, the biotin derivative is desthiobiotin. In some embodiments, the tagging comprises reacting an alkyne group of at least one tagged reactive amino acid residue with a compound comprising both an azide moiety (or other alkyne-reactive 20 group) and a detectable labeling group (e.g., biotin or a biotin derivative). In some embodiments, the compound comprising the azide moiety and the detectable labeling group further comprises an alkylene linker, which in some embodiments, can comprise a polyether group, such as an oligomer of methylene glycol, ethylene glycol or propylene glycol (e.g., a group having the formula –(O-C2H4-)x-). In some embodiments, the tagging comprises performing a copper-catalyzed azide-alkyne cycloaddition 25 (CuAAC) coupling reaction. In some embodiments, the analyzing further comprises digesting the protein sample to provide a digested protein sample comprising a protein fragment comprising the at least one tagged reactive amino acid residue comprising the detectable group. In some embodiments, the digesting is performed with a peptidase. In some embodiments, the digesting is performed with trypsin. 30 In some embodiments, the analyzing further comprises enriching the digested protein sample for the detectable labeling group. For example, in some embodiments, the enriching comprises contacting the digested protein sample with a solid support comprising a binding partner of the detectable labeling group. In some embodiments, when the detectable labeling group comprises biotin or a derivative thereof, the solid support comprises streptavidin. In some embodiments, the analyzing 35 further comprises analyzing the digested protein sample (e.g., the enriched digested protein sample) via liquid chromatography-mass spectrometry or via a gel-based assay. - 55 - Attorney Docket No.: 3436 / 3 PCT In some embodiments, providing the protein sample further comprises separating the protein sample into a first protein sample and a second protein sample. Then, in the contacting step, the first protein sample can be contacted with a first probe compound (e.g., a probe compound of Formula (I)) at a first probe concentration for a first period of time and the second protein sample can be contacted 5 with a second probe compound (e.g., a second probe compound of Formula (I) having a different structure than that of the first probe compound) at the same probe concentration (i.e., at the first probe concentration) for the same time period (i.e., for the first period of time. Alternatively, the second protein sample can be contacted with the same probe compound as the first protein sample, but at a different probe concentration (i.e., a second probe concentration) or for a different period of time. In 10 some embodiments, analyzing proteins comprises analyzing the first and second protein samples to determine the presence and / or identity of a modified reactive amino acid residue in the first sample and the presence and / or identity of a modified reactive amino acid residue in the second sample. In some embodiments, the identities and / or amounts of identified modified reactive amino acid residues from the first and second protein samples are compared. 15 In some embodiments, the protein sample comprises living cells. In some embodiments, providing the protein sample further comprises separating the protein sample into a first protein sample and a second protein sample and culturing the first protein sample in a first cell culture medium comprising heavy isotopes prior to the contacting of step (b) and culturing the second protein sample in a second cell culture medium, wherein the second culture medium comprises a naturally occurring 20 isotope distribution prior to the contacting of step (b). In some embodiments, the first cell culture medium comprises13C- and / or15N-labeled amino acids. In some embodiments, the first cell culture medium comprises13C-,15N-labeled lysine and arginine. In some embodiments, e.g., if the protein sample does not comprise living cells, the probe compound can comprise a detectable labeling group comprising a heavy isotope (e.g., a13C label) or 25 the method can comprise tagging the at least one modified amino acid residue with a detectable labeling group comprising a heavy isotope. In some embodiments, the protein sample is separated into a first and a second protein sample and one of the first and the second protein sample is cultured in the presences of an inhibitor of a protein of interest (e.g., a serine hydrolase). 30 In some embodiments, the presently disclosed subject matter provides a modified protein or protein fragment that comprises one or more amino acid residues comprising -S(=O)2-R1moiety (e.g., a -S(=O)2-phenyl or -S(=O)2-substituted phenyl moiety). V. Cells, Analytical Techniques, and Instrumentation In some embodiments, one or more of the methods disclosed herein comprise a sample (e.g., a 35 cell sample, cell lysate sample or a biological organism). In some embodiments, the sample for use with the methods described herein is obtained from cells of an animal. In some instances, the animal cell - 56 - Attorney Docket No.: 3436 / 3 PCT includes a cell from a marine invertebrate, fish, insects, amphibian, reptile, or mammal. In some instances, the mammalian cell is a primate, ape, equine, bovine, porcine, canine, feline, or rodent. In some instances, the mammal is a primate, ape, dog, cat, rabbit, ferret, or the like. In some cases, the rodent is a mouse, rat, hamster, gerbil, hamster, chinchilla, or guinea pig. In some embodiments, the 5 bird cell is from a canary, parakeet or parrots. In some embodiments, the reptile cell is from a turtles, lizard or snake. In some cases, the fish cell is from a tropical fish. In some cases, the fish cell is from a zebrafish (e.g. Danino rerio). In some cases, the worm cell is from a nematode (e.g. C. elegans). In some cases, the amphibian cell is from a frog. In some embodiments, the arthropod cell is from a tarantula or hermit crab. 10 In some embodiments, the sample for use with the methods described herein is obtained from a mammalian cell. In some instances, the mammalian cell is an epithelial cell, connective tissue cell, hormone secreting cell, a nerve cell, a skeletal muscle cell, a blood cell, or an immune system cell. Exemplary mammalian cell lines include, but are not limited to, 293A cells, 293FT cells, 293F cells, 293H cells, HEK 293 cells, CHO DG44 cells, CHO-S cells, CHO-K1 cells, and PC12 cells. 15 In some embodiments, the sample for use with the methods described herein is obtained from cells of a tumor cell line. In some instances, the sample is obtained from cells of a solid tumor cell line. In some instances, the solid tumor cell line is a sarcoma cell line. In some instances, the solid tumor cell line is a carcinoma cell line. In some embodiments, the sarcoma cell line is obtained from a cell line of alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, 20 chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, esthesioneuroblastoma, Ewing sarcoma, extrarenal rhabdoid tumor, extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory 25 myofibroblastic tumor, Kaposi sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymoma, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoid liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasms with perivascular epitheioid cell differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm with 30 perivascular epitheioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET / extraskeletal Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and telangiectatic osteosarcoma. In some embodiments, the carcinoma cell line is obtained from a cell line of adenocarcinoma, 35 squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder - 57 - Attorney Docket No.: 3436 / 3 PCT cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of Unknown Primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach 5 cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, or vulvar cancer. In some instances, the sample is obtained from cells of a hematologic malignant cell line. In some instances, the hematologic malignant cell line is a T-cell cell line. In some instances, B-cell cell line. In some instances, the hematologic malignant cell line is obtained from a T-cell cell line of: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, 10 angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T-cell lymphomas, or treatment-related T-cell lymphomas. In some instances, the hematologic malignant cell line is obtained from a B-cell cell line of: 15 acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), high-risk chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, 20 nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid 25 granulomatosis. In some embodiments, the sample for use with the methods described herein is obtained from a tumor cell line. Exemplary tumor cell lines include, but are not limited to, 600MPE, AU565, BT-20, BT-474, BT-483, BT-549, Evsa-T, Hs578T, MCF-7, MDA-MB-231, SkBr3, T-47D, HeLa, DU145, PC3, LNCaP, A549, H1299, NCI-H460, A2780, SKOV-3 / Luc, Neuro2a, RKO, RKO-AS45-1, HT-29, 30 SW1417, SW948, DLD-1, SW480, Capan-1, MC / 9, B72.3, B25.2, B6.2, B38.1, DMS 153, SU.86.86, SNU-182, SNU-423, SNU-449, SNU-475, SNU-387, Hs 817.T, LMH, LMH / 2A, SNU-398, PLHC-1, HepG2 / SF, OCI-Ly1, OCI-Ly2, OCI-Ly3, OCI-Ly4, OCI-Ly6, OCI-Ly7, OCI-Ly10, OCI-Ly18, OCI- Ly19, U2932, DB, HBL-1, RIVA, SUDHL2, TMD8, MEC1, MEC2, 8E5, CCRF-CEM, MOLT-3, TALL-104, AML-193, THP-1, BDCM, HL-60, Jurkat, RPMI 8226, MOLT-4, RS4, K-562, KASUMI- 35 1, Daudi, GA-10, Raji, JeKo-1, NK-92, and Mino. - 58 - Attorney Docket No.: 3436 / 3 PCT In some embodiments, the sample for use in the methods is from any tissue or fluid from an individual. Samples include, but are not limited to, tissue (e.g. connective tissue, muscle tissue, nervous tissue, or epithelial tissue), whole blood, dissociated bone marrow, bone marrow aspirate, pleural fluid, peritoneal fluid, central spinal fluid, abdominal fluid, pancreatic fluid, cerebrospinal fluid, brain fluid, 5 ascites, pericardial fluid, urine, saliva, bronchial lavage, sweat, tears, ear flow, sputum, hydrocele fluid, semen, vaginal flow, milk, amniotic fluid, and secretions of respiratory, intestinal or genitourinary tract. In some embodiments, the sample is a tissue sample, such as a sample obtained from a biopsy or a tumor tissue sample. In some embodiments, the sample is a blood serum sample. In some embodiments, the sample is a blood cell sample containing one or more peripheral blood mononuclear cells (PBMCs). 10 In some embodiments, the sample contains one or more circulating tumor cells (CTCs). In some embodiments, the sample contains one or more disseminated tumor cells (DTC, e.g., in a bone marrow aspirate sample). In some embodiments, the samples are obtained from the individual by any suitable means of obtaining the sample using well-known and routine clinical methods. Procedures for obtaining tissue 15 samples from an individual are well known. For example, procedures for drawing and processing tissue sample such as from a needle aspiration biopsy is well-known and is employed to obtain a sample for use in the methods provided. Typically, for collection of such a tissue sample, a thin hollow needle is inserted into a mass such as a tumor mass for sampling of cells that, after being stained, will be examined under a microscope. 20 In some embodiments, the sample is a biological organism. In some embodiments, the biological organism is a rodent, e.g., a mouse or a rat. In some embodiments, the biological organism is a primate, e.g., a monkey. In some embodiments, the biological organism is a bacteria or a fungi. VI. Sample Preparation and Analysis In some embodiments, the sample (e.g., cell sample, cell lysate sample, or comprising isolated 25 proteins) is a sample solution. In some instances, the sample solution comprises a solution such as a buffer (e.g. phosphate buffered saline) or a media. In some embodiments, the media is an isotopically labeled media. In some instances, the sample solution is a cell solution. In some embodiments, the sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) is incubated with one or more compound probes for analysis of protein-probe interactions. In 30 some instances, the sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) is further incubated in the presence of an additional compound probe prior to addition of the one or more probes. In other instances, the sample (e.g., cell sample, cell lysate sample, or comprising isolated proteins) is further incubated with a non-probe small molecule ligand, in which the non-probe small molecule ligand does not contain a photoreactive moiety and / or an alkyne group. In such instances, the 35 sample is incubated with a probe and non-probe small molecule ligand for competitive protein profiling analysis. - 59 - Attorney Docket No.: 3436 / 3 PCT In some cases, the sample is compared with a control. In some cases, a difference is observed between a set of probe protein interactions between the sample and the control. In some instances, the difference correlates to the interaction between the small molecule fragment and the proteins. In some embodiments, one or more methods are utilized for labeling a sample (e.g. cell sample, 5 cell lysate sample, or comprising isolated proteins) for analysis of probe protein interactions. In some instances, a method comprises labeling the sample (e.g. cell sample, cell lysate sample, or comprising isolated proteins) with an enriched media. In some cases, the sample (e.g. cell sample, cell lysate sample, or comprising isolated proteins) is labeled with isotope-labeled amino acids, such as13C or15N- labeled amino acids. In some cases, the labeled sample is further compared with a non-labeled sample 10 to detect differences in probe protein interactions between the two samples. In some instances, this difference is a difference of a target protein and its interaction with a small molecule ligand in the labeled sample versus the non-labeled sample. In some instances, the difference is an increase, decrease or a lack of protein-probe interaction in the two samples. In some instances, the isotope-labeled method is termed SILAC, stable isotope labeling using amino acids in cell culture. 15 In some embodiments, a method comprises incubating a sample (e.g. cell sample, cell lysate sample, or comprising isolated proteins) with a labeling group (e.g., an isotopically labeled labeling group) to tag one or more proteins of interest for further analysis. In such cases, the detectable labeling group comprises a biotin, a streptavidin, bead, resin, a solid support, or a combination thereof, and further comprises a linker that is optionally isotopically labeled. As described above, the linker can be 20 about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more residues in length and might further comprise a cleavage site, such as a protease cleavage site (e.g., TEV cleavage site). In some cases, the labeling group is a biotin-linker moiety, which is optionally isotopically labeled with13C and15N atoms at one or more amino acid residue positions within the linker. In some cases, the biotin-linker moiety is a isotopically- labeled TEV-tag as previously described.1025 In some embodiments, an isotopic reductive dimethylation (ReDi) method is utilized for processing a sample. In some cases, the ReDi labeling method involves reacting peptides with formaldehyde to form a Schiff base, which is then reduced by cyanoborohydride. This reaction dimethylates free amino groups on N-termini and lysine side chains and monomethylates N-terminal prolines. In some cases, the ReDi labeling method comprises methylating peptides from a first 30 processed sample with a “light” label using reagents with hydrogen atoms in their natural isotopic distribution and peptides from a second processed sample with a “heavy” label using deuterated formaldehyde and cyanoborohydride. Subsequent proteomic analysis (e.g., mass spectrometry analysis) based on a relative peptide abundance between the heavy and light peptide version might be used for analysis of probe-protein interactions. 35 In some embodiments, isobaric tags for relative and absolute quantitation (iTRAQ) method is utilized for processing a sample. In some cases, the iTRAQ method is based on the covalent labeling of - 60 - Attorney Docket No.: 3436 / 3 PCT the N-terminus and side chain amines of peptides from a processed sample. In some cases, reagent such as 4-plex or 8-plex is used for labeling the peptides. In some embodiments, the probe-protein complex is further conjugated to a chromophore, such as a fluorophore. In some instances, the probe-protein complex is separated and visualized utilizing an 5 electrophoresis system, such as through a gel electrophoresis, or a capillary electrophoresis. Exemplary gel electrophoresis includes agarose based gels, polyacrylamide based gels, or starch based gels. In some instances, the probe-protein is subjected to a native electrophoresis condition. In some instances, the probe-protein is subjected to a denaturing electrophoresis condition. In some instances, the probe-protein after harvesting is further fragmentized to generate protein 10 fragments. In some instances, fragmentation is generated through mechanical stress, pressure, or chemical means. In some instances, the protein from the probe-protein complexes is fragmented by a chemical means. In some embodiments, the chemical means is a protease. Exemplary proteases include, but are not limited to, serine proteases such as chymotrypsin A, penicillin G acylase precursor, dipeptidase E, DmpA aminopeptidase, subtilisin, prolyl oligopeptidase, D-Ala-D-Ala peptidase C, 15 signal peptidase I, cytomegalovirus assemblin, Lon-A peptidase, peptidase Clp, Escherichia coli phage KIF endosialidase CIMCD self-cleaving protein, nucleoporin 145, lactoferrin, murein tetrapeptidase LD-carboxypeptidase, or rhomboid-1; threonine proteases such as ornithine acetyltransferase; cysteine proteases such as TEV protease, amidophosphoribosyltransferase precursor, gamma-glutamyl hydrolase (Rattus norvegicus), hedgehog protein, DmpA aminopeptidase, papain, bromelain, cathepsin 20 K, calpain, caspase-1, separase, adenain, pyroglutamyl-peptidase I, sortase A, hepatitis C virus peptidase 2, sindbis virus-type nsP2 peptidase, dipeptidyl-peptidase VI, or DeSI-1 peptidase; aspartate proteases such as beta-secretase 1 (BACE1), beta-secretase 2 (BACE2), cathepsin D, cathepsin E, chymosin, napsin-A, nepenthesin, pepsin, plasmepsin, presenilin, or renin; glutamic acid proteases such as AfuGprA; and metalloproteases such as peptidase_M48. 25 In some instances, the fragmentation is a random fragmentation. In some instances, the fragmentation generates specific lengths of protein fragments, or the shearing occurs at particular sequence of amino acid regions. In some instances, the protein fragments are further analyzed by a proteomic method such as by liquid chromatography (LC) (e.g. high performance liquid chromatography), liquid chromatography- 30 mass spectrometry (LC-MS), matrix-assisted laser desorption / ionization (MALDI-TOF), gas chromatography-mass spectrometry (GC-MS), capillary electrophoresis-mass spectrometry (CE-MS), or nuclear magnetic resonance imaging (NMR). In some embodiments, the LC method is any suitable LC methods well known in the art, for separation of a sample into its individual parts. This separation occurs based on the interaction of the 35 sample with the mobile and stationary phases. Since there are many stationary / mobile phase combinations that are employed when separating a mixture, there are several different types of - 61 - Attorney Docket No.: 3436 / 3 PCT chromatography that are classified based on the physical states of those phases. In some embodiments, the LC is further classified as normal-phase chromatography, reverse-phase chromatography, size- exclusion chromatography, ion-exchange chromatography, affinity chromatography, displacement chromatography, partition chromatography, flash chromatography, chiral chromatography, and 5 aqueous normal-phase chromatography. In some embodiments, the LC method is a high performance liquid chromatography (HPLC) method. In some embodiments, the HPLC method is further categorized as normal-phase chromatography, reverse-phase chromatography, size-exclusion chromatography, ion-exchange chromatography, affinity chromatography, displacement chromatography, partition chromatography, 10 chiral chromatography, and aqueous normal-phase chromatography. In some embodiments, the HPLC method of the present disclosure is performed by any standard techniques well known in the art. Exemplary HPLC methods include hydrophilic interaction liquid chromatography (HILIC), electrostatic repulsion-hydrophilic interaction liquid chromatography (ERLIC) and reverse phase liquid chromatography (RPLC). 15 In some embodiments, the LC is coupled to a mass spectroscopy as a LC-MS method. In some embodiments, the LC-MS method includes ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS), ultra-performance liquid chromatography-electro spray ionization tandem mass spectrometry (UPLC-ESI-MS / MS), reverse phase liquid chromatography-mass spectrometry (RPLC-MS), hydrophilic interaction liquid 20 chromatography-mass spectrometry (HILIC-MS), hydrophilic interaction liquid chromatography-triple quadrupole tandem mass spectrometry (HILIC-QQQ), electrostatic repulsion-hydrophilic interaction liquid chromatography-mass spectrometry (ERLIC-MS), liquid chromatography time-of-flight mass spectrometry (LC-QTOF-MS), liquid chromatography-tandem mass spectrometry (LC-MS / MS), multidimensional liquid chromatography coupled with tandem mass spectrometry (LC / LC-MS / MS). In 25 some instances, the LC-MS method is LC / LC-MS / MS. In some embodiments, the LC-MS methods of the present disclosure are performed by standard techniques well known in the art. In some embodiments, the GC is coupled to a mass spectroscopy as a GC-MS method. In some embodiments, the GC-MS method includes two-dimensional gas chromatography time-of-flight mass spectrometry (GC*GC-TOFMS), gas chromatography time-of-flight mass spectrometry (GC-QTOF- 30 MS) and gas chromatography-tandem mass spectrometry (GC-MS / MS). In some embodiments, CE is coupled to a mass spectroscopy as a CE-MS method. In some embodiments, the CE-MS method includes capillary electrophoresis-negative electrospray ionization- mass spectrometry (CE-ESI-MS), capillary electrophoresis-negative electrospray ionization- quadrupole time of flight-mass spectrometry (CE-ESI-QTOF-MS) and capillary electrophoresis- 35 quadrupole time of flight-mass spectrometry (CE-QTOF-MS). - 62 - Attorney Docket No.: 3436 / 3 PCT In some embodiments, the nuclear magnetic resonance (NMR) method is any suitable method well known in the art for the detection of one or more cysteine binding proteins or protein fragments disclosed herein. In some embodiments, the NMR method includes one dimensional (1D) NMR methods, two dimensional (2D) NMR methods, solid state NMR methods and NMR chromatography. 5 Exemplary 1D NMR methods include1Hydrogen,13Carbon,15Nitrogen,17Oxygen,19Fluorine, 31Phosphorus,39Potassium,23Sodium,33Sulfur,87Strontium,27Aluminium,43Calcium,35Chlorine, 37Chlorine,63Copper,65Copper,57Iron,25Magnesium,199Mercury or67Zinc NMR method, distortionless enhancement by polarization transfer (DEPT) method, attached proton test (APT) method and 1D- incredible natural abundance double quantum transition experiment (INADEQUATE) method. 10 Exemplary 2D NMR methods include correlation spectroscopy (COSY), total correlation spectroscopy (TOCSY), 2D-INADEQUATE, 2D-adequate double quantum transfer experiment (ADEQUATE), nuclear overhauser effect spectroscopy (NOSEY), rotating-frame NOE spectroscopy (ROESY), heteronuclear multiple-quantum correlation spectroscopy (HMQC), heteronuclear single quantum coherence spectroscopy (HSQC), short range coupling and long range coupling methods. Exemplary15 solid state NMR method include solid state13Carbon NMR, high resolution magic angle spinning (HR- MAS) and cross polarization magic angle spinning (CP-MAS) NMR methods. Exemplary NMR techniques include diffusion ordered spectroscopy (DOSY), DOSY-TOCSY and DOSY-HSQC. In some embodiments, the results from the mass spectroscopy method are analyzed by an algorithm for protein identification. In some embodiments, the algorithm combines the results from the 20 mass spectroscopy method with a protein sequence database for protein identification. In some embodiments, the algorithm comprises ProLuCID algorithm, Probity, Scaffold, SEQUEST, or Mascot. In accordance with the presently disclosed subject matter, as described above or as discussed in the EXAMPLES below, there can be employed conventional chemical, cellular, histochemical, biochemical, molecular biology, microbiology, recombinant DNA, and clinical techniques which are 25 known to those of skill in the art. Such techniques are explained fully in the literature. See for example, Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Publications, Cold Spring Harbor, New York, United States of America; Glover (1985) DNA Cloning: A Practical Approach. Oxford Press, Oxford; Gait (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press, Oxford, England; Harlow & Lane, 1988, Antibodies, A Laboratory Manual, Cold 30 Spring Harbor Publications, New York; Roe et al. (1996) DNA Isolation and Sequencing: Essential Techniques, John Wiley, New York, New York, United States of America; and Ausubel et al. (1995) Current Protocols in Molecular Biology, Greene Publishing. VII. Kits / Articles of Manufacture Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one 35 or more methods described herein. In some embodiments, described herein is a kit for generating a protein comprising a detectable group and / or a fragment of a ligand compound described herein. In - 63 - Attorney Docket No.: 3436 / 3 PCT some embodiments, such kit includes a probe or ligand as described herein, small molecule fragments or libraries, and / or controls, and reagents suitable for carrying out one or more of the methods described herein. In some instances, the kit further comprises samples, such as a cell sample, and suitable solutions such as buffers or media. In some embodiments, the kit further comprises recombinant proteins for use 5 in one or more of the methods described herein. In some embodiments, additional components of the kit comprises a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, plates, syringes, and test tubes. In one embodiment, the containers are formed from a variety of 10 materials such as glass or plastic. The articles of manufacture provided herein contain packaging materials. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, bags, containers, and any packaging material suitable for a selected formulation and intended mode of use. For example, the container(s) include probes, ligands, control compounds, and one or more reagents for use in a method 15 disclosed herein. The presently disclosed kits and articles of manufacture optionally include an identifying description or label or instructions relating to its use in the methods described herein. For example, a kit typically includes labels listing contents and / or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. In some embodiments, a label 20 is on or associated with the container. In some embodiments, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In some embodiments, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the 25 contents, such as in the methods described herein. EXAMPLES The following EXAMPLES provide illustrative embodiments. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following EXAMPLES are intended to be exemplary only and that numerous changes, modifications, and alterations can be 30 employed without departing from the scope of the presently disclosed subject matter. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative EXAMPLES, make and utilize the compounds of the presently disclosed subject matter and practice the methods of the presently disclosed subject matter. The following EXAMPLES therefore particularly point out embodiments of the presently disclosed 35 subject matter and are not to be construed as limiting in any way the remainder of the disclosure. - 64 - Attorney Docket No.: 3436 / 3 PCT EXAMPLE 1 SuPUR Compound Synthesis General compounds preparation: As shown in Scheme 2 below, to a solution of purine analog (1.0 equivalent) in anhydrous DMF (5-10 mL) was added Et3N (1.0 equivalent) and sulfonyl chloride 5 analog (1.0 equivalent). The reaction mixture was stirred for 2-6 hours at room temperature. Subsequently, the organic mixture was diluted with EtOAc, which was washed with saturated brine three times. The organic solution was dried by Na2SO4and was concentrated by evaporator. The crude product was purified by a silica gel column (elution phase: EtOAc and Hexanes) to afford the SuPUR compounds. 10 Scheme 2: Synthesis of SuPUR Compounds: Reagents and Conditions: (a) DMF, K2CO3, 2-6 hours, Room Temperature General SuPUR ligands preparation was shown as Scheme 2 above. To a solution of purine (1.0 equivalent) in anhydrous DMF was added K2CO3(2.0 equivalent) and sulfonyl chloride materials 15 (1.0 equivalent). The reaction mixture was stirred for 0.5-5 hours at room temperature. Subsequently, the organic mixture was diluted with EtOAc, which was washed with saturated brine three times. The organic solution was dried by Na2SO4and was concentrated by evaporator. The crude product was purified by a silica gel column (elution phase: Hexanes and EtOAc) to afford the sulfonyl purine SuPUR ligands. 20 7-(phenylsulfonyl)-7H-purine (ZH-1-049-2). White solid. Yield 26%.1H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 9.15 (s, 1H), 8.62 (s, 1H), 7.99 (d, J = 7.5 Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H).13C NMR (125 MHz, CDCl3) δ 161.28, 155.31, 146.11, 142.26, 136.68, 135.87, 130.33, 127.45, 122.84. HRMS (ESI): calcd. for C11H8N4O2S [M+Na]+283.0260, found 283.0260. 25 9-(phenylsulfonyl)-9H-purine (ZH-2-055). White solid. Yield 6%.1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 9.03 (s, 1H), 8.49 (s, 1H), 8.24 (d, J = 7.9 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.8 Hz, - 65 - Attorney Docket No.: 3436 / 3 PCT 2H).13C NMR (125 MHz, CDCl3) δ 154.28, 150.04, 149.82, 142.48, 136.67, 135.60, 134.49, 129.70, 128.63. HRMS (ESI): calcd. for C11H8N4O2S [M+H]+261.0441, found 261.0444. 1-(phenylsulfonyl)-1H-imidazo[4,5-b]pyridine (ZH-2-036). White solid. Yield 52%.1H NMR (400 5 MHz, DMSO-d6) δ 9.16 (d, J = 2.7 Hz, 1H), 8.55 (dd, J = 4.8, 1.5 Hz, 1H), 8.34 (dd, J = 8.2, 1.6 Hz, 1H), 8.23 – 8.17 (m, 2H), 7.78 (t, J = 7.5 Hz, 1H), 7.66 (t, J = 7.8 Hz, 2H), 7.47 (dd, J = 8.2, 4.8 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 156.09, 147.31, 145.24, 136.69, 136.25, 130.78, 127.86, 123.50, 121.58, 121.28. HRMS (ESI): calcd. for C12H9N3O2S [M+Na]+282.0308, found 282.0310. 10 7-((2-(trifluoromethoxy)phenyl)sulfonyl)-7H-purine (ZH-2-097). White solid. Yield 24%.1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 1.4 Hz, 1H), 9.22 (d, J = 1.3 Hz, 1H), 9.15 (d, J = 1.4 Hz, 1H), 8.51 (dd, J = 8.0, 1.7 Hz, 1H), 7.96 (td, J = 8.0, 1.7 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.65 – 7.59 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ 161.13, 155.25, 148.41, 145.91, 145.89, 142.38, 139.38, 132.61, 128.85, 127.91, 123.85, 123.10, 121.63, 121.61, 121.59, 121.25, 118.65.19F NMR (375 MHz, DMSO- 15 d6) δ -55.87. HRMS (ESI): calcd. for C12H7F3N4O3S [M+Na]+367.0083, found 367.0088. 9-((2-(trifluoromethoxy)phenyl)sulfonyl)-9H-purine (ZH-2-098). White solid. Yield 6%.1H NMR (500 MHz, CDCl3) δ 9.10 (s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 8.48 (dd, J = 8.0, 1.7 Hz, 1H), 7.71 (td, J = 8.5, 1.7 Hz, 1H), 7.56 – 7.49 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H).13C NMR (125 MHz, CDCl3) δ 154.28, 20 149.95, 149.83, 146.55, 143.28, 137.49, 134.31, 133.09, 128.42, 127.02, 123.09, 121.00, 120.27, 120.25, 120.23, 118.91, 116.83.19F NMR (470 MHz, CDCl3) δ -56.59. HRMS (ESI): calcd. for C12H7F3N4O3S [M+Na]+345.0264, found 345.0258. 7-((2,6-dichlorophenyl)sulfonyl)-7H-purine (ZH-2-025). White solid. Yield 28%.1H NMR (400 MHz,25 DMSO-d6) δ 9.48 (s, 1H), 9.16 (s, 1H), 9.10 (s, 1H), 7.78 – 7.72 (m, 3H).13C NMR (100 MHz, DMSO- - 66 - Attorney Docket No.: 3436 / 3 PCT d6) δ 161.14, 155.25, 149.33, 142.05, 137.43, 135.76, 133.38, 131.08, 130.76, 123.56. HRMS (ESI): calcd. for C11H6Cl2N4O2S [M+Na]+350.9481, found 350.9486. 7-((2-(trifluoromethyl)phenyl)sulfonyl)-7H-purine (ZH-2-103). White solid. Yield 43%.1H NMR (400 5 MHz, DMSO-d6) δ 9.30 (d, J = 3.8 Hz, 2H), 9.16 (d, J = 1.6 Hz, 1H), 8.70 – 8.66 (m, 1H), 8.12 (d, J = 6.2 Hz, 1H), 8.08 – 8.01 (m, 2H).13C NMR (100 MHz, DMSO-d6) δ 161.14, 155.20, 148.62, 142.51, 137.19, 135.06, 133.57, 130.16, 130.10, 130.04, 129.96, 123.27.19F NMR (470 MHz, DMSO-d6) δ - 56.18. HRMS (ESI): calcd. for C12H7F3N4O2S [M+Na]+351.0134, found 351.0137. 10 1-((2-(trifluoromethoxy)phenyl)sulfonyl)-1H-imidazo[4,5-c]pyridine (ZH-5-037). White solid. Yield 52%.1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.85 (s, 1H), 8.51 – 8.41 (m, 2H), 7.93 (q, J = 7.1, 6.5 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.67 – 7.53 (m, 2H).13C NMR (100 MHz, DMSO-d6) δ 145.56, 143.89, 143.63, 140.38, 139.23, 135.81, 132.59, 132.47, 128.80, 121.61, 107.68.19F NMR (375 MHz, DMSO-d6) δ -55.89. HRMS (ESI): calcd. for C13H8F3N3O3S [M+H]+344.0311, found 344.0304. 15 3-((2-(trifluoromethoxy)phenyl)sulfonyl)-3H-imidazo[4,5-b]pyridine (ZH-5-039-1). White solid. Yield 39%.1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.43 (dd, J = 8.0, 1.7 Hz, 1H), 8.30 (dd, J = 4.9, 1.4 Hz, 1H), 8.22 (dd, J = 8.1, 1.5 Hz, 1H), 7.91 (ddd, J = 8.3, 7.6, 1.7 Hz, 1H), 7.72 (td, J = 7.8, 1.0 Hz, 1H), 7.58 – 7.53 (m, 1H), 7.40 (dd, J = 8.1, 4.8 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ 20 146.46, 145.59, 144.74, 143.41, 142.22, 138.81, 135.64, 133.22, 129.70, 128.47, 121.53, 121.26, 118.61.19F NMR (375 MHz, DMSO-d6) δ -55.77. HRMS (ESI): calcd. for C13H8F3N3O3S [M+Na]+366.0131, found 366.0127. 1-((2-(trifluoromethoxy)phenyl)sulfonyl)-1H-imidazo[4,5-b]pyridine (ZH-5-039-2). White solid. 25 Yield 39%.1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 1.7 Hz, 1H), 8.54 (dt, J = 5.1, 1.7 Hz, 1H), 8.44 (dt, J = 8.0, 1.8 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.97 – 7.87 (m, 1H), 7.70 (t, J = 7.7 Hz, 1H), - 67 - Attorney Docket No.: 3436 / 3 PCT 7.59 (d, J = 8.2 Hz, 1H), 7.41 (ddd, J = 8.4, 4.9, 1.8 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 155.88, 147.43, 145.69, 145.18, 139.11, 132.37, 128.80, 128.14, 123.43, 121.62, 121.30, 121.24, 121.15.19F NMR (375 MHz, DMSO-d6) δ -55.87. HRMS (ESI): calcd. for C13H8F3N3O3S [M+Na]+366.0131, found 366.0125. 5 4-( purin-9-yl)sulfonyl)benzonitrile (ZH-2-029). White solid. Yield 8%.1H NMR (500 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.14 (s, 2H), 8.49 (d, J = 8.2 Hz, 2H), 8.26 (d, J = 8.2 Hz, 2H).13C NMR (125 MHz, DMSO-d6) δ 154.39, 150.22, 150.14, 144.37, 140.30, 134.53, 129.47, 118.48, 117.60. HRMS (ESI): calcd. for C12H7N5O2S [M+Na]+308.0013, found 308.0214. 10 4-((7H-purin-7-yl)sulfonyl)benzonitrile (ZH-2-030). White solid. Yield 16%.1H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.45 (s, 1H), 9.20 (s, 1H), 8.55 (d, J = 8.2 Hz, 2H), 8.23 (d, J = 8.2 Hz, 2H). 13C NMR (125 MHz, DMSO-d6) δ 161.33, 155.28, 148.47, 142.78, 140.13, 134.81, 132.56, 129.16, 126.88, 123.04, 118.63, 117.56. HRMS (ESI): calcd. for C12H7N5O2S [M+H]+286.0393, found 15 286.0393. 4-((3H-imidazo[4,5-b]pyridin-3-yl)sulfonyl)benzonitrile (ZH-5-055-1). White solid. Yield 9%.1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.45 (dd, J = 4.9, 1.5 Hz, 1H), 8.40 (d, J = 8.4 Hz, 2H), 8.23 (dd, J = 8.1, 1.5 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 7.46 (dd, J = 8.1, 4.8 Hz, 1H).13C NMR (100 20 MHz, DMSO-d6) δ 146.52, 144.88, 143.33, 140.70, 135.91, 134.42, 129.76, 129.26, 121.65, 118.18, 117.63. HRMS (ESI): calcd. for C13H8N4O2S [M+H]+285.0441, found 285.0432. - 68 - Attorney Docket No.: 3436 / 3 PCT 4-((1H-imidazo[4,5-b]pyridin-1-yl)sulfonyl)benzonitrile (ZH-5-055-2). White solid. Yield 56%.1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 0.7 Hz, 1H), 8.57 (dd, J = 4.8, 0.8 Hz, 1H), 8.39 (ddd, J = 14.7, 8.6, 0.8 Hz, 3H), 8.16 (d, J = 8.1 Hz, 2H), 7.52 – 7.43 (m, 1H).13C NMR (100 MHz, DMSO-d6) δ 5 156.08, 147.50, 145.27, 140.41, 134.80, 128.69, 123.47, 121.66, 121.44, 118.41, 117.54. HRMS (ESI): calcd. for C13H8N4O2S [M+Na]+307.0260, found 307.0258. 4-((1H-imidazo[4,5-c]pyridin-1-yl)sulfonyl)benzonitrile (ZH-5-057). White solid. Yield 32%.1H NMR (500 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.05 (s, 1H), 8.58 (d, J = 5.7 Hz, 1H), 8.44 (d, J = 8.2 Hz, 2H), 10 8.18 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 5.6 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 145.70, 143.92, 143.61, 140.27, 135.85, 134.83, 128.74, 118.50, 117.53, 108.11. HRMS (ESI): calcd. for C13H8N4O2S [M+H]+285.0441, found 285.0437. 4-((7H-purin-7-yl)sulfonyl)-N-phenethylbenzamide (ZH-2-077). White solid. Yield 18%.1H NMR 15 (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.39 (s, 1H), 9.15 (s, 1H), 8.83 (t, J = 5.6 Hz, 1H), 8.40 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 8.7 Hz, 2H), 7.28 – 7.11 (m, 5H), 3.45 (q, J = 6.8 Hz, 2H), 2.79 (t, J = 7.3 Hz, 2H).13C NMR (100 MHz, DMSO-d6) δ 164.86, 161.26, 155.21, 148.45, 142.72, 141.50, 139.70, 138.13, 129.38, 129.08, 128.79, 128.59, 126.59, 122.91, 41.44, 35.24. HRMS (ESI): calcd. for C20H17N5O3S [M+Na]+430.0944, found 430.0947. - 69 - Attorney Docket No.: 3436 / 3 PCT 4-((9H-purin-9-yl)sulfonyl)-N-phenethylbenzamide (ZH-2-078). White solid. Yield 13%.1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.03 (s, 1H), 9.01 (s, 1H), 8.78 (t, J = 5.5 Hz, 1H), 8.28 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.25 – 7.07 (m, 5H), 3.41 (q, J = 6.8 Hz, 2H), 2.75 (t, J = 7.4 Hz, 5 2H).13C NMR (125 MHz, DMSO-d6) δ 164.99, 154.35, 150.19, 150.07, 144.39, 141.50, 139.74, 138.35, 134.49, 129.12, 129.10, 128.92, 128.80, 126.60, 41.46, 35.29. HRMS (ESI): calcd. for C20H17N5O3S [M+Na]+430.0944, found 430.0937. 4-((3H-imidazo[4,5-b]pyridin-3-yl)sulfonyl)-N-phenethylbenzamide (ZH-5-049-1). White solid. Yield 10 12%.1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.80 (t, J = 5.8 Hz, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.42 (dd, J = 8.1, 4.9 Hz, 1H), 7.29 – 7.10 (m, 5H), 3.43 (q, J = 6.8 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H).13C NMR (125 MHz, DMSO-d6) δ 165.10, 146.47, 144.93, 143.35, 141.19, 139.74, 138.79, 135.91, 129.66, 129.11, 128.99, 128.81, 128.75, 126.61, 121.53, 41.46, 35.29. HRMS (ESI): calcd. for C21H18N4O3S [M+Na]+429.0992, 15 found 429.0984. 4-((1H-imidazo[4,5-b]pyridin-1-yl)sulfonyl)-N-phenethylbenzamide (ZH-5-049-2). White solid. Yield 48%.1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.79 (t, J = 5.5 Hz, 1H), 8.54 (dd, J = 4.8, 1.5 Hz, 1H), 8.33 (dd, J = 8.2, 1.5 Hz, 1H), 8.29 (d, J = 8.5 Hz, 2H), 8.01 – 7.91 (m, 2H), 7.45 (dd, J = 8.2, 4.8 20 Hz, 1H), 7.32 – 7.05 (m, 5H), 3.42 (q, J = 6.9 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H).13C NMR (125 MHz, - 70 - Attorney Docket No.: 3436 / 3 PCT DMSO-d6) δ 164.98, 156.12, 147.42, 145.25, 141.33, 139.72, 138.49, 129.36, 129.10, 128.81, 128.18, 126.61, 123.49, 121.63, 121.36, 41.46, 35.27. HRMS (ESI): calcd. for C21H18N4O3S [M+Na]+429.0992, found 429.0984. 5 4-((1H-imidazo[4,5-c]pyridin-1-yl)sulfonyl)-N-phenethylbenzamide (ZH-5-051). White solid. Yield 46%.1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 9.09 (s, 1H), 8.80 (t, J = 5.5 Hz, 1H), 8.53 (t, J = 5.6 Hz, 1H), 8.32 (dd, J = 19.3, 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 5.4 Hz, 1H), 7.30 – 7.05 (m, 5H), 3.42 (q, J = 6.7 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H).13C NMR (125 MHz, DMSO-d6) δ 164.98, 149.34, 145.92, 145.22, 141.42, 139.73, 138.35, 135.35, 129.40, 129.11, 128.81, 128.34, 10 128.32, 126.61, 116.01, 41.47, 35.26. HRMS (ESI): calcd. for C21H18N4O3S [M+H]+407.1172, found 407.1167. 7-((4-chlorophenyl)sulfonyl)-7H-purine (ZH-2-058). White solid. Yield 24%.1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.38 (s, 1H), 9.15 (s, 1H), 8.34 – 8.31 (m, 2H), 7.80 – 7.74 (m, 2H).13C NMR 15 (100 MHz, DMSO-d6) δ 161.25, 155.17, 148.43, 142.71, 141.80, 135.08, 131.00, 130.35, 122.93. HRMS (ESI): calcd. for C16H15N5O3S [M+Na]+316.9870, found 316.9877. 7-((2,6-dibromophenyl)sulfonyl)-7H-purine (ZH-2-101). Gray solid. Yield 41%.1H NMR (400 MHz, DMSO-d6) δ 9.43 (d, J = 1.3 Hz, 1H), 9.16 (d, J = 1.4 Hz, 1H), 9.05 (d, J = 1.3 Hz, 1H), 8.01 (dd, J = 20 8.2, 1.4 Hz, 2H), 7.51 (t, J = 8.0 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 161.06, 155.26, 149.52, 142.00, 137.70, 137.60, 133.49, 124.11, 123.51. HRMS (ESI): calcd. for C11H6Br2N4O2S [M+Na]+438.8470, found 438.8482. - 71 - Attorney Docket No.: 3436 / 3 PCT 3-(phenylsulfonyl)-3H-imidazo[4,5-b]pyridine (ZH-5-019). White solid. Yield 12%.1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.43 (dd, J = 4.9, 1.5 Hz, 1H), 8.24 – 8.15 (m, 3H), 7.76 (t, J = 7.5 Hz, 1H), 7.65 (t, J = 7.8 Hz, 2H), 7.42 (dd, J = 8.1, 4.8 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 146.38, 5 144.94, 143.34, 136.97, 136.01, 135.87, 130.34, 129.53, 128.44, 121.37. HRMS (ESI): calcd. for C12H9N3O2S [M+H]+260.0488, found 260.0485. 1-(phenylsulfonyl)-1H-imidazo[4,5-c]pyridine (ZH-5-021). White solid. Yield 38%.1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.54 (dd, J = 4.8, 1.5 Hz, 1H), 8.32 (dd, J = 8.2, 1.5 Hz, 1H), 8.19 (d, 10 J = 7.2 Hz, 2H), 7.77 (t, J = 7.5 Hz, 1H), 7.65 (t, J = 7.9 Hz, 2H), 7.45 (dd, J = 8.2, 4.8 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 143.95, 142.85, 136.92, 135.92, 130.65, 130.53, 127.68, 126.14, 125.40, 121.17, 112.82. HRMS (ESI): calcd. for C12H9N3O2S [M+H]+260.0488, found 260.0484. An exemplary approach to general sulfonyl ligand preparation is shown as Scheme 3 below. Summarily, To a solution of purine (1.0 equivalent) in anhydrous CH3CN was added Et3N (2.0 15 equivalent) and sulfonyl chloride materials (1.0 equivalent). The reaction mixture was stirred for 0.5-5 hours at room temperature. Subsequently, the organic mixture was diluted with EtOAc, which was washed with saturated brine three times. The organic solution was dried by Na2SO4and was concentrated by evaporator. The crude product was purified by a silica gel column (elution phase: Hexanes and EtOAc) to afford the SuPUR ligands. 20 Scheme 3: Synthesis of sulfonyl purine ligands; Reagents and conditions: (a) CH3CN, Et3N, rt, 0.5-5 hours - 72 - Attorney Docket No.: 3436 / 3 PCT 9-tosyl-9H-purine (ZH-1-049-0). White solid. Yield 43%.1H NMR (600 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.36 (s, 1H), 9.14 (s, 1H), 8.19 – 8.17 (m, 2H), 7.50 – 7.48 (m, 2H), 2.36 (s, 3H).13C NMR (200 MHz, DMSO-d6) δ 160.76, 154.65, 147.97, 147.40, 142.24, 132.92, 130.83, 127.85, 122.40, 21.17. 5 HRMS (ESI): calcd. for C12H10N4O2S [M+Na]+297.0417, found 297.0424. 7-((4'-methoxy-[1,1'-biphenyl]-4-yl)sulfonyl)-7H-purie (ZH-2-017). White solid. Yield 37%.1H NMR (400 MHz, DMSO-d6) δ 9.51 – 9.46 (m, 1H), 9.44 – 9.39 (m, 1H), 9.18 – 9.11 (m, 1H), 8.32 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 3.78 (s, 3H).13C 10 NMR (100 MHz, DMSO-d6) δ 161.23, 160.75, 155.13, 148.48, 147.47, 142.75, 133.86, 130.11, 129.18, 129.02, 128.08, 122.93, 115.10, 55.76. HRMS (ESI): calcd. for C18H14N4O3S [M+Na]+389.0679, found 389.0687. 7-((4-fluorophenyl)sulfonyl)-7H-purine (ZH-2-018). White solid. Yield 29%.1H NMR (400 MHz, DMSO-d6) δ15 9.46 (s, 1H), 9.38 (s, 1H), 9.15 (s, 1H), 8.43 – 8.39 (m, 2H), 7.54 (d, J = 8.8 Hz, 2H).13C NMR (100 MHz, DMSO- d6) δ 167.99, 165.44, 161.22, 155.15, 148.42, 142.72, 132.59, 132.05, 131.95, 122.90, 118.39, 118.16. HRMS (ESI): calcd. for C11H7FN4O2S [M+Na]+301.0166, found 301.0170. 9-(m-tolylsulfonyl)-9H-purine (ZH-2-019). White solid. Yield 36%.1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 20 1H), 9.36 (s, 1H), 9.13 (s, 1H), 8.14 – 8.05 (m, 2H), 7.64 – 7.50 (m, 2H), 2.36 (s, 3H).13C NMR (100 MHz, DMSO-d6) δ 155.11, 148.43, 142.74, 141.11, 137.24, 136.20, 130.62, 128.20, 126.50, 125.43, 123.05, 21.08. HRMS (ESI): calcd. for C12H10N4O2S [M+Na]+297.0417, found 297.0416. - 73 - Attorney Docket No.: 3436 / 3 PCT N-(4-((9H-purin-9-yl)sulfonyl)phenyl)acetamide (ZH-2-020). White solid. Yield 33%.1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.41 (d, J = 1.6 Hz, 1H), 9.31 (d, J = 1.6 Hz, 1H), 9.14 (d, J = 1.6 Hz, 1H), 8.23 – 8.16 (m, 2H), 7.85 – 7.79 (m, 2H).13C NMR (100 MHz, DMSO-d6) δ 168.80, 149.99, 149.24, 143.18, 141.96, 139.89, 5 130.00, 128.62, 126.55, 119.58, 118.98, 118.26, 24.48. HRMS (ESI): calcd. for C13H11N5O3S [M+Na]+340.0475, found 340.0475. 7-(thiophen-2-ylsulfonyl)-7H-purine (ZH-2-022). White solid. Yield 26%.1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 9.37 (s, 1H), 9.16 (s, 1H), 8.35 (dd, J = 4.0, 1.4 Hz, 1H), 8.25 (dd, J = 4.9, 1.4 Hz, 1H), 7.30 (dd, J = 4.9, 10 4.0 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 161.25, 155.23, 148.33, 142.59, 139.87, 138.21, 135.26, 129.76, 122.74. HRMS (ESI): calcd. for C9H6N4O2S2[M+Na]+288.9824, found 288.9827. 9-((4-bromophenyl)sulfonyl)-9H-purine (ZH-2-023). White solid. Yield 18%.1H NMR (500 MHz, DMSO-d6) δ 9.35 – 9.25 (m, 1H), 9.07 (q, J = 3.9 Hz, 2H), 8.22 – 8.15 (m, 2H), 7.95 (m, 2H).13C NMR (125 MHz, DMSO- 15 d6) δ 154.32, 150.15, 150.03, 144.36, 135.66, 134.51, 133.66, 130.93, 130.65. HRMS (ESI): calcd. for C11H7BrN4O2S [M+Na]+360.9365, found 360.9366. 9-tosyl-9H-purin-6-amine (ZH-1-069). White solid. Yield 10%.1H NMR (600 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.18 (s, 1H), 8.08 – 8.05 (m, 2H), 7.60 (s, 2H), 7.49 – 7.47 (m, 2H), 2.37 (s, 3H).13C NMR (200 MHz, DMSO- 20 d6) δ 156.32, 154.37, 148.34, 146.67, 138.12, 133.58, 130.33, 128.05, 118.74, 21.19. HRMS (ESI): calcd. for C12H11N5O2S [M+Na]+312.0532, found 312.0526. - 74 - Attorney Docket No.: 3436 / 3 PCT 7-((phenylsulfonyl)methyl)-7H-purine (ZH-2-026). White solid. Yield 14%.1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.25 (t, J = 7.5 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 5.42 (s, 2H).13C NMR (125 MHz, DMSO-d6) δ 160.27, 154.65, 148.51, 142.48, 131.29, 129.94, 129.24, 127.22, 5 124.02, 60.50, HRMS (ESI): calcd. for C12H10N4O2S [M+Na]+297.0417, found 297.0415. 7-(naphthalen-1-ylsulfonyl)-7H-purine (ZH-2-027). White solid. Yield 31%.1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.35 (s, 1H), 9.11 (s, 1H), 8.91 (d, J = 7.5 Hz, 1H), 8.73 (d, J = 8.7 Hz, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.82 (td, J = 7.6, 3.9 Hz, 2H), 7.72 (t, J = 7.5 Hz, 1H).13C NMR (125 MHz, DMSO-d6) 10 δ 161.26, 155.11, 148.73, 142.54, 138.49, 134.30, 133.17, 130.59, 130.46, 128.33, 127.21, 125.57, 122.97, 122.86. calcd. for C15H10N4O2S [M+Na]+333.0417, found 333.0413. 1-(phenylsulfonyl)-1H-benzo[d]imidazole (ZH-2-035). White solid. Yield 46%.1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.16 (d, J = 7.8 Hz, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.65 (t, J = 7.6 Hz, 2H), 15 7.40 (dt, J = 22.4, 7.5 Hz, 2H).13C NMR (100 MHz, DMSO-d6) δ 143.95, 142.86, 136.93, 135.94, 130.67, 130.54, 127.70, 126.16, 125.42, 121.18, 112.84. HRMS (ESI): calcd. for C13H10N2O2S [M+H]+259.0536, found 259.0542. 4-((7H-purin-7-yl)sulfonyl)benzaldehyde (ZH-2-039). White solid. Yield 36%.1H NMR (400 MHz, DMSO-d6) δ 10.07 (d, J = 1.4 Hz, 1H), 9.47 (d, J = 1.5 Hz, 1H), 9.42 (d, J = 1.4 Hz, 1H), 9.16 (d, J = 1.5 Hz, 1H), 8.51 (dq, 20 J = 8.7, 2.0 Hz, 2H), 8.17 – 8.11 (m, 2H).13C NMR (101 MHz, DMSO-d6) δ 192.76, 161.29, 155.25, 148.50, 142.71, 141.13, 140.45, 131.29, 129.76, 129.18, 126.67, 122.94. HRMS (ESI): calcd. for C12H8N4O3S [M+Na]+311.0209, found 311.0211. - 75 - Attorney Docket No.: 3436 / 3 PCT 4-((7H-purin-7-yl)sulfonyl)-N-(cyclopropylmethyl)benzamide (ZH-2-053, 70% N7 and 30% N9). Yellow solid. Yield 26%.1H NMR (400 MHz, DMSO-d6) δ 9.42 (d, J = 20.5 Hz, 1H), 9.05 (d, J = 9.3 Hz, 1H), 8.82 (t, J = 5.6 Hz, 1H), 8.43 – 8.30 (m, 2H), 8.06 (dd, J = 8.4, 5.7 Hz, 2H), 3.09 (ddd, J = 7.3, 5.6, 2.1 Hz, 2H), 1.01 – 0.89 (m, 5 1H), 0.35 (ddt, J = 8.2, 4.0, 2.2 Hz, 2H), 0.15 (dq, J = 4.2, 2.1 Hz, 2H). HRMS (ESI): calcd. for C16H15N5O3S [M+H]+358.0968, found 358.0969. 4-((9H-purin-9-yl)sulfonyl)-N-cyclopropylbenzamide (ZH-2-067, 50% N7 and 50% N9). White solid. Yield 25%. 101H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J = 10.0 Hz, 1H), 9.06 (d, J = 10.7 Hz, 1H), 8.69 (d, J = 4.0 Hz, 1H), 8.39 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.01 (t, J = 7.1 Hz, 2H), 2.87 – 2.76 (m, 1H), 0.67 (d, J = 7.0 Hz, 2H), 0.57 – 0.44 (m, 2H). HRMS (ESI): calcd. for C15H13N5O3S [M+Na]+366.0631, found 366.0632. (1-(4-((7H-purin-7-yl)sulfonyl)benzoyl)piperidin-4-yl)(phenyl)methanone (ZH-2-069). White solid. Yield 23%. 151H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.39 (s, 1H), 9.13 (s, 1H), 8.34 (d, J = 8.1 Hz, 2H), 7.95 (d, J = 7.7 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 4.42 (d, J = 13.0 Hz, 1H), 3.72 (d, J = 11.6 Hz, 1H), 3.15 (s, 1H), 2.97 (t, J = 12.7 Hz, 1H), 1.86 (d, J = 13.2 Hz, 1H), 1.64 (d, J = 12.8 Hz, 1H), 1.49 (d, J = 12.6 Hz, 2H).13C NMR (100 MHz, DMSO-d6) δ 202.20, 167.19, 161.19, 155.08, 148.42, 143.80, 142.70, 136.69, 135.77, 133.66, 128.82, 128.65, 123.00, 42.69, 42.58, 41.30, 28.82, 28.43. HRMS (ESI): calcd. 20 for C24H21N5O4S [M+Na]+498.1206, found 498.1200. - 76 - Attorney Docket No.: 3436 / 3 PCT 4-((7H-purin-7-yl)sulfonyl)-N-benzylbenzamide (ZH-2-071). White solid. Yield 16%.1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.40 (s, 1H), 9.31 (t, J = 6.1 Hz, 1H), 9.15 (s, 1H), 8.44 – 8.38 (m, 2H), 8.13 – 8.07 (m, 2H), 7.33 – 7.18 (m, 5H), 4.45 (d, J = 5.9 Hz, 2H).13C NMR (100 MHz, DMSO-d6) δ 164.90, 161.27, 155.21, 5 148.45, 142.72, 141.19, 139.43, 138.28, 129.56, 128.76, 128.61, 127.66, 127.33, 122.91, 43.24. HRMS (ESI): calcd. for C19H15N5O3S [M+Na]+416.0788, found 416.0791. 4-((7H-purin-7-yl)sulfonyl)-N-phenylbenzamide (ZH-2-073). White solid. Yield 28%.1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.50 (s, 1H), 9.44 (s, 1H), 9.17 (s, 1H), 8.50 – 8.43 (m, 2H), 8.16 – 8.10 (m, 2H), 7.69 10 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H).13C NMR (101 MHz, DMSO-d6) δ 164.32, 161.31, 155.26, 148.52, 142.76, 142.08, 139.04, 138.36, 129.98, 129.17, 129.04, 128.52, 127.75, 125.93, 124.65, 122.89, 120.81, 120.77. HRMS (ESI): calcd. for C18H13N5O3S [M+Na]+402.0631, found 402.0636. 7-((3-bromophenyl)sulfonyl)-7H-purine (ZH-2-075). White solid. Yield 32%.1H NMR (500 MHz, DMSO-d6) δ 15 9.46 (s, 1H), 9.36 (s, 1H), 9.11 (s, 1H), 8.49 (t, J = 1.9 Hz, 1H), 8.29 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.97 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H).13C NMR (125 MHz, DMSO) δ 161.26, 155.21, 148.51, 142.84, 139.44, 138.21, 132.82, 130.59, 127.55, 123.58, 123.02. HRMS (ESI): calcd. for C11H7BrN4O2S [M+Na]+360.9365, found 360.9363. 20 9-((2-chlorophenyl)sulfonyl)-9H-purine (ZH-2-085). White solid. Yield 47%.1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.22 (s, 1H), 9.15 (s, 1H), 8.60 (dd, J = 8.3, 1.6 Hz, 1H), 7.85 – 7.81 (m, 1H), 7.75 – 7.71 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 155.25, 149.32, 142.33, 138.24, 133.32, 133.16, 132.19, 129.36, 123.03. HRMS (ESI): calcd. for C11H7ClN4O2S [M+Na]+316.9870, found 316.9872. - 77 - Attorney Docket No.: 3436 / 3 PCT 7-(o-tolylsulfonyl)-7H-purine (ZH-2-086). White solid. Yield 48%.1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.21 (s, 1H), 9.11 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 2.50 (s, 3H).13C NMR (100 MHz, DMSO-d6) δ 161.27, 155.03, 148.53, 142.26, 138.79, 136.61, 5 134.12, 130.83, 128.14, 123.05, 20.13. HRMS (ESI): calcd. for C12H10N4O2S [M+Na]+297.0417, found 297.0419. 7-((2-bromophenyl)sulfonyl)-7H-purine (ZH-2-093). White solid. Yield 19%.1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.19 (s, 1H), 9.14 (s, 1H), 8.62 (dd, J = 7.8, 1.8 Hz, 1H), 7.90 (dd, J = 7.7, 1.4 Hz, 1H), 7.75 (ddd, J 10 = 11.7, 7.6, 1.6 Hz, 2H).13C NMR (100 MHz, DMSO-d6) δ 161.21, 155.24, 149.44, 142.32, 138.08, 136.86, 135.04, 133.51, 129.84, 123.01, 120.67. HRMS (ESI): calcd. for C11H7BrN4O2S [M+Na]+360.9365, found 360.9371. 7-((2-fluorophenyl)sulfonyl)-7H-purine (ZH-2-095). White solid. Yield 34%.1H NMR (500 MHz, DMSO-d6) δ 15 9.40 (s, 1H), 9.30 (s, 1H), 9.18 (s, 1H), 8.38 (td, J = 7.7, 1.7 Hz, 1H), 7.92 (tdd, J = 7.8, 5.1, 1.7 Hz, 1H), 7.61 – 7.50 (m, 2H).13C NMR (125 MHz, DMSO-d6) δ 161.28, 160.14, 158.09, 155.22, 148.58, 148.56, 142.47, 139.87, 139.80, 131.39, 126.52, 126.50, 124.23, 124.13, 123.19, 118.78, 118.62.19F NMR (470 MHz, DMSO-d6) δ - 108.37. HRMS (ESI): calcd. for C11H7FN4O2S [M+Na]+301.0166, found 301.0167. 20 7-((2,6-dimethoxyphenyl)sulfonyl)-7H-purine (ZH-2-099). White solid. Yield 19%.1H NMR (400 MHz, DMSO- d6) δ 9.23 (s, 1H), 9.09 (s, 1H), 9.02 (s, 1H), 7.60 (t, J = 8.5 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 3.78 (s, 6H).13C NMR (100 MHz, DMSO-d6) δ 160.98, 159.55, 154.72, 149.55, 141.98, 138.30, 123.64, 112.52, 105.98, 57.38. HRMS (ESI): calcd. for C13H12N4O4S [M+Na]+343.0471, found 343.0475. 25 - 78 - Attorney Docket No.: 3436 / 3 PCT 7-((4-bromo-2,5-difluorophenyl)sulfonyl)-7H-purine (ZH-2-105). White solid. Yield 47%.1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 9.31 (s, 1H), 9.15 (d, J = 1.7 Hz, 1H), 8.41 (dd, J = 7.6, 6.1 Hz, 1H), 8.12 (dd, J = 9.7, 5.3 Hz, 1H).13C NMR (100 MHz, DMSO-d6) δ 161.26, 155.17, 148.35, 142.65, 124.19, 123.94, 123.29, 118.75, 5 118.46.19F NMR (470 MHz, DMSO-d6) δ -109.32, -111.45. HRMS (ESI): calcd. for C11H5BrF2N4O2S [M+Na]+396.9177, found 396.9183. 10 7-((2,6-difluorophenyl)sulfonyl)-7H-purine (ZH-2-115). White solid. Yield 72%.1H NMR (400 MHz, DMSO- d6) δ 9.36 (d, J = 1.3 Hz, 1H), 9.17 (d, J = 1.6 Hz, 2H), 7.94 – 7.87 (m, 1H), 7.42 (t, J = 9.0 Hz, 2H).19F NMR (375 MHz, DMSO-d6) δ -106.40.13C NMR (101 MHz, DMSO-d6) δ 161.16, 160.73, 158.14, 155.23, 148.51, 142.28, 140.04, 139.92, 139.81, 123.50, 114.94, 114.92, 114.89, 114.74, 114.71, 114.69. HRMS (ESI): calcd. for 319.0072, found 319.0076. 15 4-((6-oxo-1,6-dihydro-7H-purin-7-yl)sulfonyl)-N-(prop-2-yn-1-yl)benzamide (ZH-1-142). White solid. Yield 20%.1H NMR (600 MHz, DMSO-d6) δ 12.78 (d, J = 4.0 Hz, 1H), 9.22 (t, J = 5.5 Hz, 1H), 8.60 (s, 1H), 8.28 – 8.25 (m, 2H), 8.14 (d, J = 3.9 Hz, 1H), 8.09 – 8.05 (m, 2H), 4.04 (dd, J = 5.5, 2.6 Hz, 2H), 3.13 (t, J = 2.5 Hz, 1H). HRMS (ESI): calcd. for C15H11N5O4S [M+Na]+380.0424, found 20 380.0427. 4-((2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)sulfonyl)-N-(prop-2-yn-1-yl)benzamide (ZH-1-143). White solid. Yield 12%.1H NMR (600 MHz, DMSO-d6) δ 9.32 – 9.16 (m, 2H), 8.25 – 8.16 (m, 2H), - 79 - Attorney Docket No.: 3436 / 3 PCT 8.07 – 7.99 (m, 2H), 7.72 (s, 1H), 7.04 (s, 1H), 4.09 – 3.99 (m, 2H), 3.12 (t, J = 2.5 Hz, 1H). HRMS (ESI): calcd. for C15H11N5O5S [M+Na]+396.0373, found 396.0375 EXAMPLE 2 Biological Methods 5 Cell culture. Cell lines were cultured at 37 °C with 5% CO2with manufacturer recommended media supplemented with 10% fetal bovine serum (US Source, Omega Scientific) and 1% L-glutamine (Fisher Scientific): HEK293T: DMEM. Cells were collected or treated for experimental use when they reached ∼90% confluency. The media was aspirated, cells washed with cold PBS (2×) and scraped from plates. The cells were pelleted by centrifugation at 400g for 5 min, snap-frozen using liquid nitrogen 10 and stored at −80 °C until further use. Gel-Based Chemical Proteomic Assay (rhodamine-azide). Cell pellets were lysed in PBS by sonication and fractionated (100,000g, 45 min, 4 °C) to generate soluble and membrane fractions. Protein concentrations were determined using the Bio-Rad DC protein assay and adjusted to 1 mg ml-1in PBS. Proteome samples (48 µl aliquots) were treated with SuPUR ligands or probe at the indicated 15 concentrations (1 µl, 50× stock in DMSO) for 1 h at room temperature. Probe-labeled samples were conjugated by copper-catalyzed azide-alkyne cycloaddition (CuAAC) to rhodamine-azide (1 µl of 1.25 mM stock; final concentration of 25 µM), tris(2-carboxyethyl)phosphine (TCEP; 1 µl of fresh 50 mM stock in water, final concentration of 1 mM), tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA, 3 µl of a 1.7 mM 4:1 t-butanol / DMSO stock, final concentration of 100 µM) and copper sulfate 20 (CuSO4, 1 µl of 50 mM stock, final concentration of 1 mM). Samples were reacted for 1 h at room temperature, quenched with 17 µl of 4x SDS–PAGE loading buffer and ß-mercaptoethanol (ßME) and quenched samples (30 µl) analyzed by SDS–PAGE and in-gel fluorescence scanning. Gel-Based Chemical Proteomic Assay (fluorophosphonate-rhodamine, FP-Rh). Cell pellets were lysed in PBS by sonication and fractionated (100,000g, 45 min, 4 °C) to generate soluble and 25 membrane fractions. Protein concentrations were determined using the Bio-Rad DC protein assay and adjusted to 1 mg ml-1in PBS. Proteome samples (48 µl aliquots) were treated with SuPUR ligand or fluorophosphonate-rhodamine (FP-Rh, 1 µl of 50 µM stock; final concentration of 1 µM). Samples were reacted for 1 h at room temperature, quenched with 16.7 µl of 4x SDS–PAGE loading buffer and ß- mercaptoethanol (ßME) and quenched samples (30 µl) analyzed by SDS–PAGE and in-gel fluorescence 30 scanning. Live cell evaluation of probes. Cells grown to ~90% confluency in 10 cm plates were treated with DMSO vehicle or probe (10 µl of 1,000× DMSO stock) in serum-free media for the indicated concentrations and times at 37 °C with 5% CO2. After treatment, cells were washed with cold PBS twice before collection and preparation for gel-based chemical proteomic evaluation as described above. For - 80 - Attorney Docket No.: 3436 / 3 PCT LC–MS studies, protein concentrations were normalized to 2.3 mg ml-1and 432 µl (for 1 mg final protein amount) were used for sample preparation as detailed below. Preparation of proteomes for tandem mass tag LC-MS / MS chemical proteomics. For in situ treatments, live cells were treated with 100 µM probe (37 °C, 5% CO2) for 4 hours, harvested, then 5 diluted and aliquots of soluble proteome (1 mg) utilized for LC-MS / MS sample preparation. For in vitro treatments, soluble proteome (1 mg) was incubated with 100 µM probe (1hr, 37 °C). Copper-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) and chloroform / methanol extractions were used to remove click reagents as previously described. See Franks et al., Cell Chem. Biol.2017, 24(7), 870-880; Hahm et al., Nat. Chem. Biol. 2020, 16(2), 150-159. Following resuspension in 6M Urea / 25mM AmBic, 10 proteins were reduced by dithiothreitol and alkylated with iodoacetamide as previously described. See Franks et al., Cell Chem. Biol. 2017, 24(7), 870-880. Denaturing reagents were removed via chloroform / methanol extraction. Proteins were digested overnight with Tryp-Lys-C in 25mM AmBic (7.5 µg, 37 °C). Streptavidin enrichment of modified peptides. SuPUR-modified peptides were enriched with 15 avidin agarose and eluted using 150 µL of 50% ACN + 0.1% formic acid (3X) and stored at -80 °C until analysis. FP-Rh Competition. Cell soluble or membrane proteome fraction (1 mg / mL) was incubated with SuPUR compound for 1 hour at 37 °C followed by incubation with 1 µM FP-Rh (1 hour, room temperature). Results were determined by gel-based scanning and LC-MS / MS analysis. 20 LC–MS / MS analysis of samples. Nano-electrospray ionization–LC–MS / MS analyses were performed using an Ultimate 3000 RSLC nanoSystem-Orbitrap Q Exactive Plus mass spectrometer (Thermo Scientific) as previously described (see Franks et al. (2017) Cell Chemical Biology 24(7):870- 880) except LC conditions were modified to use the following gradient (A, 0.1% formic acid / H2O; B, 80% MeCN, 0.1% formic acid in H2O): 0–1.48 min 1% B, 400 nL min-1; 1.48–2:00 min 1% B, 300  25 nL min-1; 2–90 min 16% B; 90–14625% B; 146–147 min 95% B; 147–153 min 95% B; 153–154 min 1% B; 154.0–154.1 min 1% B, 400 nL min-1; 154.1–180 min 1% B, 400  nL min-1. A top ten data- dependent acquisition MS method was used. LC–MS / MS data analysis. Identification of peptides and proteins from tandem mass spectrometry analyses was accomplished using the Byonic software package (Protein Metrics Inc.; see 30 Bern et al. (2012) Current Protocols in Bioinformatics 13, Unit 1320.). Data were searched against a modified human protein database (UniProt human protein database, angiotensin I and vasoactive intestinal peptide standards; 40,660 proteins) with the following parameters: up to three missed cleavages to account for a lysine probe modification, 10 ppm precursor mass tolerance, 20 ppm fragment mass tolerance, too high (narrow) ‘precursor isotope off by x’, precursor and charge 35 assignment computed from MS1, maximum of one precursor per MS2, 0.01 smoothing width, 1% protein false discovery rate, variable (common) methionine oxidation (+15.9949 Da) and fixed cysteine - 81 - Attorney Docket No.: 3436 / 3 PCT carbamidomethylation (+57.021464 Da). Search results were filtered for a Byonic score of >300 (unless otherwise specified), a Delta Mod score of >20, and a precursor mass error between −5 and +5 ppm. A Byonic score of 300 was applied for a more inclusive initial evaluation of the search results and thereby consider more possible probe-modified sites. 5 Analysis and comparison of probe-modified amino acid sites. To compare amino acid residues modified by electrophilic probes, protein and peptide identifications were accomplished as described above on the following amino acid residues: cysteine, aspartic acid, glutamic acid, histidine, lysine, methionine, asparagine, glutamine, arginine, serine, threonine, tryptophan and tyrosine. For these amino acid comparisons, carbamidomethylation (+57.021464 Da) of cysteines was searched as a 10 variable / common modification to allow for the potential of probe modification on cysteines. Venn diagrams for comparisons were generated using InteractiVenn.net. See Heberle et al. (2015) BMC Bioinformatics 16(1):169. For amino acid comparisons, a Byonic score cutoff of 300 was used to minimize false positive identifications of modified residues, which were confirmed by manual evaluation to be incorrect assignments. 15 NAD bioluminescent assay (sold under the tradename NAD / NADH-GLO™; Promega Corporation, Madison, Wisconsin, United States of America). 1. ABAD enzyme to the desired enzyme concentration based on the specific activity of the enzyme lot.20 μL of diluted enzyme (20 nM) was added to each well along with 2.5 μL of 10X inhibitor solution; 20 2. Assay plate was incubated at RT for 30 minutes, and then 2.5 μL of a 20X estradiol / 20X NAD+mix was added to each well for a final concentration of 50 μM estradiol and 500 μM NAD+. The assay plate was incubated at 37oC for 3 hours; 3. Detection system reagents (sold under the tradename NAD(P)H-GLO™ Detection System; Promega Corporation, Madison, Wisconsin, United States of America) were prepared according to 25 manufacturer’s specifications, and 25 μL was added to each well. After incubating for 1 hour at RT, luminescence was measured using BioTek 5. WST-1 assay. 1. Plate cells in 96-well plates at an appropriate density (4,000-6,000 cells per well); 30 2. Incubate the cells in a humidified incubator at 37°C with 5% CO2until they adhere or reach the desired growth phase; 3. Treat cells with the experimental compounds for 48 hours; 4. After treatment, add the 10 µL WST-1 working solution to each well containing cells; 35 5. Incubate the plate in the dark at 37°C for 4 hours; - 82 - Attorney Docket No.: 3436 / 3 PCT 6. Gently mix the contents of the plate by tapping. Measure the absorbance of each well at 450 nm (with a reference wavelength of 620 nm) using BioTek 5. Discussion of the EXAMPLES 1 and 2 The binding pocket of ABAD includes a non-catalytic tyrosine. Given initial ABPP studies 5 showing that the SuPUR compounds preferentially modify tyrosine and lysine residues (see Figure 1F), additional studies were carried out to determine if the compounds could covalently modify this residue and whether Tyr168 modification could inhibit ABAD activity. Exemplary SuPUR compound ZH-1- 049-2 was active in modifying ABAD in a concentration-dependent manner. See Figure 2A. In addition, ZH-1-049-2 was reactive with wild-type ABAD, but not with a mutant ABAD where tyrosine 10 168 was changed to a glycine See Figure 2C. The presence of the tyrosine at residue 168 was important for maintaining ABAD activity. See Figure 2C. Gel-based screening using a library of SuPUR compounds (see Figure 3A) indicated that, in addition to ZH-1-049-2 (see Figure 3B), ZH-2-025 and ZH-2-029 showed concentration-dependent labeling of ABAD. See Figure 3C and 3D. ZH-2-029 and ZH-2-025 showed better reactivity for ABAD 15 compared to ZH-1-049-2. The 50% inhibitory concentrations (IC50s) of these three compounds was determined. See Figure 3E. ZH-2-025 was most effective at inhibiting the activity of ABAD, with an IC50of 430 nM. ZH-2-029 had an IC50of 571 nm and ZH-1-049-2 had an IC50of 776 nM. The initial data and subsequent modeling of ZH-2-025 in the ABAD binding pocket suggested the possibility of interactions (e.g., the formation of a halogen bond) between the ortho-chloro20 substituent in ZH-2-025 and Gly93. See Figure 4A. Thus, additional SuPUR compounds with ortho- substituted phenyl groups was studied. See Figures 4B-4D. ESP calculations of three dihalo-substituted SuPUR compounds suggested demonstrated that Cl and Br maintain a positive electrostatic potential, which is important for halogen bonds. See Figure 4E. Additional biological activity testing of ABAD and SuPUR modified ABAD was performed. 25 See Figures 5A-5I. ZH-2-025 exhibited potent binding affinity for ABAD with IC50values of 53.7 nM. See Figures 5A and 5B. ZH-2-025 and ZH-2-029 disrupted the interaction of ABAD and A^ 1-42. See Figures 5C, 5D, and 5F. ZH-2-025 exhibited cell toxicity, while ZH-2-029 exhibited moderate cell toxicity. See Figures 5E and 5G. ZH-2-029 could stabilize ABAD, particularly the dimer. See Figure 5H. ZH-2-029 was able to reduce ROS production. See Figure 5I. 30 Initial studies with ABHD10 showed that ZH-1-049-2 was also able to modify ABHD10 in a concentration-dependent manner. See Figure 6. Further studies using a library of SuPUR compounds (see Figure 7A) showed that ZH-2-025 had potent labeling activity for ABHD10. See Figures 7B and 7C. Further studies showed that ZH-2-097 and ZH-2-103 also showed potent ADHD10 labeling. See Figures 8A-8D. Based on the data and docketing studies of ZH-2-097 and ABHD10, it is believed that 35 ZH-2-097 can maintain hydrogen bonds with Tyr215, His279 and Ser152 in the ABHD10 binding - 83 - Attorney Docket No.: 3436 / 3 PCT pocket. In addition, the perfluoralkoxyl substituent of ZH-2-097 can maintain hydrogen bonds with Arg280. See Figures 9A-9C. The ability of ZH-2-097 to label other serine hydrolases was studied. See Figure10A. In addition, the binding site of ZH-2-097 in ABHD10 was further validated. See Figures 10B-10E. 5 Overall, ZH-2-097 showed very selective labelling activity for ABHD10. Introduction to EXAMPLES 3-8 Synthesis of SuPUR Probes. As an alternative strategy, SuPUR Probes of the presently disclosed subject matter can be synthesized as per Scheme 4 below. Materials were from commercial sources and were used as received. Organic solvents were concentrated via a rotary evaporator 10 (Heidolph) under reduced pressure (VARIO PC 3001) at 35 °C - 50 °C. Reactions were monitored using silica gel TLC plates (GF254, 0.25 mm) and visualized under UV (365 / 254 nm) light. Proton nuclear magnetic resonance (1H NMR) and carbon nuclear magnetic resonance (13C NMR) spectra were determined using Bruker AV-600 MHz, AV-500 MHz or Agilent 400 MHz instruments. Coupling constants are reported in Hz and multiplicities are quoted as singlet (s), doublet(d), triplet (t), quartet 15 (q), heptet (h), multiplet (m), and broad signal (bs). High-resolution mass spectra (HRMS) were recorded on an Agilent Q-Tof mass spectrometer. 20 Scheme 4: Reagents and conditions: (a) EDCI, rt, 2 hours, 49%; (b) DMF, K2CO3, rt, 1-6 hours, 13-41%. - 84 - Attorney Docket No.: 3436 / 3 PCT S1 was synthesized according to procedures described elsewhere. The1H spectrum of S1 was identical to those reported. 4-(prop-2-yn-1-ylcarbamoyl) benzenesulfonyl chloride (S1) was a white solid. General probes (AHL-PuP-2 and ZH-2-087) preparation was shown as Scheme 4 above. To a 5 solution of purine (1.0 equivalent) in anhydrous DMF (5-10 mL) was added K2CO3(2.0 equivalent) and sulfonyl chloride (S1, 1.0 equivalent). The reaction mixture was stirred for 1-6 hours at room temperature. Subsequently, the organic mixture was diluted with EtOAc, which was washed with saturated brine three times. The organic solution was dried by Na2SO4and was concentrated by evaporator. The crude product was purified by a silica gel column (elution phase: EtOAc and Hexanes) 10 to afford the probes (AHL-PuP-2 and ZH-2-087). 4-((7H-purin-7-yl)sulfonyl)-N-(prop-2-yn-1-yl)benzamide (2, AHL-PuP-2). White solid, yield 12%.1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.40 (s, 1H), 9.22 (t, J = 5.5 Hz, 1H), 9.15 (s, 1H), 8.42 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 4.03 (dd, J = 5.6, 2.6 Hz, 2H), 3.13 (t, J = 2.5 Hz, 1H).13C 15 NMR (125 MHz, DMSO-d6) δ 164.69, 161.30, 155.23, 148.47, 142.74, 140.69, 138.50, 129.59, 128.64, 122.96, 81.12, 73.73, 29.19. HRMS (ESI): calcd. for C15H11N5O3S [M+Na]+364.0475, found 364.0481. 4-((9H-purin-9-yl) sulfonyl)-N-(prop-2-yn-1-yl) benzamide (3, ZH-2-087). White solid, yield 8%.1H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.16 (t, J = 5.6 Hz, 1H), 9.03 (s, 1H), 9.01 (s, 1H), 8.30 (d, 20 J = 8.1 Hz, 2H), 8.03 (d, J = 8.1 Hz, 2H), 3.98 (dd, J = 5.7, 2.6 Hz, 2H), 3.08 (t, J = 2.6 Hz, 1H).13C NMR (125 MHz, DMSO-d6) δ 164.82, 154.35, 150.20, 150.07, 144.40, 140.65, 138.66, 134.49, 129.31, 128.98, 81.14, 73.72, 29.19. HRMS (ESI): calcd. for C15H11N5O3S [M+H]+342.0655, found 342.0655. EXAMPLE 3 Development of SuPUR Chemoproteomics 25 SuPUR probes were synthesized by sulfonylation of the purine N7 or N9 with a minimal alkynyl reporter design previously demonstrated to be compatible with tandem liquid chromatography- mass spectrometry (LC-MS / MS) analyses (see Kovalska et al. (2014) Nature Chemical Biology 16(2): - 85 - Attorney Docket No.: 3436 / 3 PCT 150-159]. It was anticipated that the purine would exhibit sufficient leaving group ability to activate SuPUR modification of proteins in a manner analogous to that reported for sulfonyl-azole chemistry {Nature chemical biology, 16(2), 150–159]. Strategic placement of the sulfonyl-purine electrophile at the N7 vs N9 position afforded opportunities for prioritizing target sites proteome-wide via 5 regioselective recognition. To assess protein labeling activity, HEK293T cell proteomes were treated with the SuPUR probes AHL-PuP-2 (N7 isomer) or ZH-2-087 (N9 isomer) followed by copper-catalyzed azide-alkyne cycloaddition (CuAAC) conjugation of rhodamine-azide and SDS-PAGE detection of fluorescent protein bands. These gel-based chemoproteomic studies demonstrated comparable concentration- and 10 time-dependent labeling activity for the SuPUR probes. Importantly, pretreatment with free purine resulted in a substantial loss of AHL-PuP-2 and ZH-2-087 probe labeling activity. Next, label-free, LC-MS / MS chemoproteomics were conducted to identify nucleophilic residues on proteins preferentially modified by SuPUR chemistry. Careful inspection of MS2 spectra from SuPUR probe-modified peptides identified y- and b-fragment ions that confidently localized 15 probe modifications on residues modified by SuPUR reaction (SuPUR adduct mass of 635.2737 Da; see Figure 11. Across the 13 nucleophilic amino acids evaluated on detectable peptides, it was determined that AHL-PuP-2 and ZH-2-087 preferentially modified tyrosine (Y, ~60%) and lysine (K, ~40%). Compared with SuTEx (see Hahm et al. (2020) Nature Chemical Biology 16(2):150-159), the SuPUR chemistry 20 appeared to show higher lysine binding preference (40% vs 25% K modifications, respectively). Binding site coverage between AHL-PuP-2 and ZH-2-087 was comparable in SuPUR probe treated proteomes (~14,000-15,000 probe-modified peptides; see Figure 12A). Comparison of binding sites labeled by each respective probe revealed overlapping (64%) but also, interestingly, distinct sites for the N7 (AHL-PuP-2, 31%) and N9 isomer SuPUR probes (ZH-2-087, 38%) that also translated into 25 distinct protein targets (see Figures 12B and 12C). Proteins that were labeled by N7- compared with N9-SuPUR probes were enriched for different biological functions as measured by Gene Ontology analyses. These data highlighted the capability of SuPUR probes for regioselective and proteome-wide assessment of targetable protein sites. The chemoproteomic profiling was expanded to five additional human cell proteomes to determine the breadth of proteomic coverage attainable with the SuPUR 30 platform. Using AHL-PuP-2, an average of about 13,000 modified sites were detected from each cell line that collectively translated to greater than 31,000 total modified sites (~50 / 50 distribution between Y and K sites) from about 4,300 proteins. This chemoproteomic dataset is believed to represent the most comprehensive database of tyrosine and lysine residues in the human proteome amenable to covalent targeting. It was further discovered that ~20% of SuPUR-modified sites resided in a predicted 35 drug pocket, providing insights into which detectable sites are likely candidates for further ligand discovery efforts. Importantly, it was determined that SuPUR chemoproteomics can capture a - 86 - Attorney Docket No.: 3436 / 3 PCT substantial fraction (41%) of the human purine interactome with coverage across multiple subclasses of purine-binding proteins (30-50%; see Figure 19). Finally, gene ontology (GO) and KEGG pathway enrichment of proteins identified by AHL- PuP-2 was performed to investigate their associated biological process(es). The top enrichments were 5 associated with cellular metabolism and RNA processing, likely due to the role of purine as an endogenous metabolite and a building block for RNA, which can mimic substrates such as ATP, GTP, NAD+, adenosine, and other purine-based metabolites. EXAMPLE 4 Deep Analysis of the SuPUR Ligandable Proteome 10 Domain enrichment analysis was performed on SuPUR-modified sites to gain a deeper understanding of proteins domains targeted. As expected, enrichment for RNA-binding regions (RRM domain) from the SuPUR-bound sites was observed given that purine is a core constituent of nitrogenous bases found in RNA. Beyond RNA, domains involved in binding ATP (protein kinase domain) and GTP (RAB domain), which are cofactors that contain a purine component, were also 15 enriched in the SuPUR dataset. To determine whether SuPUR-targeted proteins have known drugs or ligands, a comparative analysis of AHL-PuP-2 identified proteins against DrugBank and ChEMBL databases was performed. The analysis revealed that over 50% of these proteins lacked known bioactive ligands or approved drugs, suggesting that SuPUR could provide an enabling assay for developing targeted agents for 20 intractable targets or those without effective ligands. To explore purine recognition in greater depth, gel-based competitive activity-based protein profiling (ABPP) was performed to determine SuPUR probe labeling could be outcompeted with free purine pretreatment. Pretreatment with free purine resulted in concentration dependent blockade of AHL-PuP-2 and ZH-2-087 probe labeling with prominent reductions in fluorescent labeling at the 25 highest concentration tested. Importantly, competition with benzimidazole, which is a similar scaffold but lacks key nitrogen atoms for purine recognition, demonstrated a lack of inhibitory activity in the probe competition study. These findings supported purine recognition as an important factor for the observed SuPUR probe labeling in the proteome. To test whether SuPUR detected sites are ligandable regions on proteins, the N7- and N9- 30 substituted SuPUR ligands, ZH-1-049-2 and ZH-2-055, respectively, were synthesized for evaluation in a competitive tandem mass tag (TMT)-ABPP assay. To assess purine recognition, the single-nitrogen deletion (N-delete) control compounds ZH-2-036 (N7) and ZH-5-019 (N9) were synthesized and regioisomer structures confirmed by X-ray crystallography. The regioisomer structures for this ligand fragment set was further confirmed by carbon (13C) NMR analysis, which revealed detectable 35 differences in the C4 / C5 and C5 signals of the SuPUR and N-delete regioisomer pairs, respectively (see Figure 13). - 87 - Attorney Docket No.: 3436 / 3 PCT Next, SuPUR TMT-ABPP deploying AHL-PuP-2 as the detection probe was performed in HEK293T proteome to identify the targets and binding sites of ZH-1-049-2. In brief, HEK293T proteomes were pretreated with SuPUR ligand (25 µM, 1 hour) followed by SuPUR probe labeling (100 µM, 1 hour), CuAAC conjugation of desthiobiotin-azide, trypsin digestion, TMT labeling, avidin 5 chromatography, and LC-MS / MS analysis of probe-modified peptides. Among the liganded targets, TMT-ABPP analysis indicated that the SuPUR ligand ZH-1-049-2 but not the corresponding N-delete control ZH-2-036 exhibited potent covalent binding activity towards multiple druggable sites, including ABHD10 Y215, GSTP1 Y8, ABAD Y168, GNPNAT1 Y165, and PARP2 Y455 (see Figures 14A and 14B). These competition events were due to probe binding blockade and not protein expression changes 10 as evidenced by matching unenriched TMT analyses. Subsequently, SuPUR TMT-ABPP was performed using ZH-2-087 probe and the matching N9 SuPUR ligand ZH-2-055. Chemoproteomics analysis revealed that ZH-2-055 but not the N-delete ZH- 5-019 control retained potent covalent binding activity to several proteins also liganded by ZH-1-049- 2, including ABHD10, GSTP1, and ABAD (see Figures 14C and14D). Akin to studies with ZH-1-049- 15 2, changes in protein expression profiles for proteins with prominent alterations in probe competition ratios were not observed. By comparing ZH-1-049-2 and ZH-2-055 proteomic binding profiles, several liganded sites were identified including PARP2 (Y455) and GNPNAT1 (Y165) that exhibited regioselective interactions. EXAMPLE 5 20 SuPUR Fragment Ligand Binds Catalytic and Non-catalytic Sites to Disrupt Enzymatic Functions Several ZH-1-049-2-liganded sites are located within or near active sites prompting its further testing as an inhibitor of target proteins. Amyloid-β (Aβ) peptide-binding alcohol dehydrogenase (ABAD) and alpha / β-hydrolase domain containing 10 (ABHD10) were selected for initial evaluation. Covalent inhibitors of ABHD10, a serine hydrolase enzyme, are reported but inactivate principally 25 through binding the catalytic and highly conserved active site serine residue (Cao et al. (2019) Nature Chemical Biology 15(12):1232-1240). Whether covalent engagement of the non-catalytic tyrosine Y215, located near the catalytic serine S152, can block ABHD10 activity remains unknown. A gel- based competitive ABPP assay with the established activity-based probe fluorophosphonate-rhodamine (FP-Rh) was employed to evaluate ZH-1-049-2 inhibitory activity against ABHD10. The results 30 indicated that ZH-1-049-2 exhibited moderate inhibitory activity, with an IC50value of approximately 10 µM against a 34 kDa band matching the expected MW of ABHD10, Subsequently, to confirm target engagement against ABHD10 and to assess selectivity across the serine hydrolase family, a the competitive ABPP evaluation using FP-biotin and a TMT-based MS readout was performed. Quantitative ABPP analysis identified 65 serine hydrolase proteins, with ZH- 35 1-049-2 showing 40% inhibition of ABHD10 at 25 µM, while the ZH-2-036 control showed no inhibitory activity. - 88 - Attorney Docket No.: 3436 / 3 PCT Next, whether covalent binding of ZH-1-049-2 to Y168 could affect ABAD activity was tested. ABAD is a mitochondrial dehydrogenase involved in steroid metabolism and reported to interact with intracellular amyloid-beta resulting in neuronal dysfunction in Alzheimer’s disease (AD). Currently, there is a lack of potent and direct acting ABAD inhibitors (see Morsy & Trippier (2019) Journal of 5 Medicinal Chemistry 62(9):4252-4264). Evaluation of ABAD structures demonstrated that ZH-1-049- 2-liganded site Y168 is a part of a highly conserved catalytic triad in ABAD and forms hydrogen bond with its cofactor NAD+. To assess the inhibitory activity of compound ZH-1-049-2 and control ZH-2-036, an NAD(P) / NAD(P)H-Glo biochemical assay for ABAD was established. ZH-1-049-2 showed moderate 10 inhibitory activity, with an IC50of 1.45 ± 0.15 µM. In contrast, control ZH-2-036 exhibited only weak inhibitory activity, while the reported ABAD inhibitor Frentizole showed no activity at 100 µM. The ability to achieve selectively within members of an enzyme family is important for advancing fragment hits in ligand discovery programs. The activity of ZH-1-049-2 against PARP2 but not PARP1 in the presently disclosed chemoproteomic studies was intriguing given that ZH-1-049-2 15 binds the conserved Y455 site in the NAD+binding pocket of the active site that is also engaged by the clinical drug Olaparib (Wang et al. (2025) Bioorganic Chemistry 160:108471). A PARP biochemical assay was used to determine whether this SuPUR ligand could block PARP2 biochemical activity and if the compound showed preferential blockade of PARP2 vs PARP1. The result indicated that ZH-1- 049-2 showed concentration-dependent blockade of PARP2 with submicromolar potency (IC50of 273 20 nM) and negligible activity against PARP1 even at the highest concentration tested (200 µM. As expected, treatment with Olaparib under the same experimental conditions resulted in comparable and potent inactivation of PARP1 and PARP2 (IC50of ~1 nM). Taken together, it has been demonstrated that the SuPUR ligand can block diverse enzymatic functions with varying degrees of ligand efficiency (micro- to nano-molar potency) and in some cases 25 with an unexpected degree of isoform specificity. EXAMPLE 6 Rapid Optimization of an Ultrapotent and Proteome-wide Selective SuPUR ABHD10 Inhibitor The ligandability assessment of ZH-1-049-2 showed preliminary evidence that the SuPUR scaffold could be optimized into potent and selective inhibitors of diverse protein classes. Whether this 30 common fragment starting point could be rapidly progressed into distinct targeted covalent inhibitors was then assessed. If demonstrated, the SuPUR chemotype could expedite the fragment-based ligand discovery (FBLD) by reducing the number of fragment lead compounds that need to be screened at the onset of a discovery campaign. ABHD10 was pursued for initial discovery because development of a proteome-wide selective serine hydrolase inhibitor through targeting a non-catalytic tyrosine residue 35 has not been achieved to date. - 89 - Attorney Docket No.: 3436 / 3 PCT Molecular docking revealed that the terminal phenyl group of ZH-1-049-2 extends into a solvent-exposed pocket, suggesting that substituent groups could be introduced at this position to improve binding affinity. A focused library of 24 SuPUR ligands with modifications on the phenylsulfone was developed, and initial evaluation by competitive gel-based ABPP indicated that the 5 2,6-dichloro-substituted compound ZH-2-025 showed a dramatic boost in potency (30-fold) compared with ZH-1-049-2 (IC50~0.36 compared with ~12 µM for ZH-2-025 vs. ZH-1-049-2). ZH-2-025 exhibited an IC50of approximately 360 nM in HEK293T following in situ treatment. A docking study for ZH-2-025 was conducted, which identified that the chlorine atom of ZH-2-025 forms a hydrogen bond with Arg280 of ABHD10. Based on this binding modeling, small electron- 10 withdrawing or electron-donating groups were introduced at this position to disclose their impact on binding affinity. The gel-based ABPP screening demonstrated that OCF3and CF3-substituted compounds, ZH-2-097 and ZH-2-103, exhibited IC50values of less than 200 nM with in situ treatment; however, ZH-2-103 showed off target activity, as indicated on the gel data. ZH-2-097 was also evaluated by gel-based ABPP with in vitro treatment, yielding an IC50value of approximately 50 nM. 15 Therefore, further studies focusing on ZH-2-097 were conducted. In addition, to investigate the impact of regio-isomers on ABHD10 binding affinity, the 9- positioned sulfonyl derivative ZH-2-098 was synthesized, and the regio-isomer was further confirmed by crystal structures. Gel-ABPP showed that both compounds exhibited potent activity with IC50of about 50 nM. The docking model identified that ZH-2-097 could occupy the serine catalytic pocket, 20 with OCF3group forming hydrogen bonds with Tyr87. To further confirm the binding affinity of ZH-2-097 to ABHD10 in HEK293T soluble and membrane proteome with in situ treatment, gel-ABPP was performed. It was determined that ZH-2-097 exhibited potent activity against ABHD10 with IC50values less than 200 nM (i.e., 132.4 ± 67.3 nM for the soluble fraction and 171.9 ± 57.2 nM for the membrane fraction), with no significant off-targets. 25 While not wishing to be bound by any particular theory of operation, it is believed that the SuPUR ligands disclosed herein inhibited ABHD10 activity by targeting a non-catalytic tyrosine rather than the canonical catalytic serine. This finding is indicative of a novel mechanism of action against ABHD10. ZH-2-097 functions as a “lock” by covalently binding to Tyr215, thereby locking the serine catalytic pocket and disrupting the recruitment of its substrate (Figure 15). 30 To assess the selectivity of ZH-2-097 in serine hydrolase families, MS-based ABPP was conducted to identify its targets in the HEK293T proteome using FP-biotin with in situ treatment. The MS analysis identified 65 serine hydrolases, and ZH-2-097 demonstrated remarkable selectivity with a dose-dependent inhibition of ABHD10 (Figure 16). ZH-2-097 still maintained excellent selectivity even when considering all 1770 proteins detectable by LC-MS / MS, and it also showed significant inhibitory 35 activity against ABHD10 compared to control ZH-2-036. - 90 - Attorney Docket No.: 3436 / 3 PCT To further confirm the binding site of ZH-2-097, ZH-2-097 competitive TMT-ABPP using the SuPUR probe AHL-PuP-2 in the HEK293T proteome was performed. The unenriched TMT data showed no significant alterations in the ABHD10 protein profile in the compound treated group compared to DMSO control group. In contrast, the enriched proteomics analysis of the probe modified 5 peptides proved that ZH-2-097 could bind to the Tyr215 site with ultra-selectivity in a dose-dependent manner (Figures 17A and 17B). Furthermore, the level of probe-modified peptide containing binding site Tyr215 exhibited significant differences when compared to control ZH-2-036. To investigate the contribution of purine to the binding of SuPUR ligands with ABHD10, compounds ZH-5-039-1, ZH-5-039-2, and ZH-5-037 were synthesized through the nitrogen walk along 10 the purine core. Gel-ABPP analysis indicated that only purine containing SuPUR ligand ZH-2-097 exhibited nanomolar binding affinity for ABHD10, highlighting the purine backbone as an important recognition group. To expand the potential for future pharmacological therapeutic applications, gel-based competitive ABPP was conducted in mouse tissue, including heart, liver, kidney, lung, spleen, and 15 brain. The results demonstrated that ZH-2-097 exhibited nanomolar activities in all tested tissues other than the liver. EXAMPLE 7 Development of an ABAD Inhibitor Using SuPUR Ligand Targeting a Catalytic Tyrosine Aβ-binding alcohol dehydrogenase (ABAD) is a key enzyme involved in steroid metabolism, 20 and its binding to Aβ is thought to contribute to the neurotoxicity. The inhibition of ABAD holds a promising therapeutic potential for the treatment of Alzheimer’s disease and various cancers. However, to date only a limited number of small molecules targeting ABAD with moderate binding affinities have been reported. Herein is presented the development of a potent ABAD inhibitor utilizing SuPUR ligand to selectively target a catalytic tyrosine. 25 First, to further confirm the binding site of AHL-PuP-2 on ABAD, the gel-based ABPP including wild-type (WT) and corresponding Y168G mutant in HEK293T proteome was performed. The result, consistent with proteomics data, demonstrated that AHL-PuP-2 exhibited high reactivity with Tyr168 residue of ABAD. Gel-based competitive ABPP was performed to evaluate the binding affinity of ZH-1-049-2 for ABAD in HEK293T proteome, yielding an IC50of approximately 5 µM. 30 ABAD is a key enzyme involved in regulating the balance between estradiol and estrone in neurons. A stable and robust biochemical assay based on NAD(P) / NAD(P)H-Glo system was developed using estradiol (E2) as the substrate. Notably, the Z’ factor of 0.549 indicated excellent assay quality, making it well-suited for high-throughput screening of ABAD inhibitors. Cofactor selectivity and the functionality of the Tyr168 residue using NAD(P) / NAD(P)H-Glo 35 assay was investigated. In this biological system, NAD+facilitates the oxidization of estradiol to estrone, while NADP+did not sustain enzyme activity, resulting in the readout value equivalent to the - 91 - Attorney Docket No.: 3436 / 3 PCT background signal without substrate estradiol. Notably, the mutation of Tyr168 to Gly168 resulted in a complete loss of catalytic activity, suggesting that Tyr168 is an essential functional residue for ABAD. SuPUR compounds could thus efficiently inhibit ABAD by selectively targeting Tyr168. Docking studies revealed that ZH-1-049-2 occupied the NAD+binding pocket, with its sulfonyl group forming 5 hydrogen bonds with Tyr168 and Lys172. And the binding pocket provides ample space to accommodate minor substations on phenyl group. The SuPUR library was then constructed by introducing small groups to the phenyl group. The library was screened by gel-based competitive ABPP and NAD(P) / NAD(P)H-Glo assay, leading to identification of a potent ligand, ZH-2-029, which exhibited inhibitory activity against ABAD with an 10 IC50of 559 ± 60 nM. To investigate the impact of regio-isomers on ABAD binding affinity, the 7-positioned sulfonyl purine ZH-2-030, was synthesized. Gel-ABPP revealed a micromolar binding affinity of ZH-2-030 for ABAD with an IC50of 2392 ± 818 nM, indicating regioselectivity for ABAD. To further investigate the role of purine core in SuPUR binding to ABAD, compounds ZH-5- 15 055-1, ZH-5-055-2, and ZH-5-057 were synthesized through the nitrogen walk along the purine scaffold. Gel-based competitive ABPP results demonstrated that only purine-containing ZH-2-029 and not ZH-5-057, ZH-5-055-1, or ZH-5-055-2 exhibited nanomolar binding affinity for ABAD, highlighting the purine backbone as a key driving force for target binding (Figure 18), NAD(P) / NAD(P)H-Glo results further confirmed that only SuPUR compounds retained potent 20 inhibitory activity against ABAD, with ZH-2-029 and ZH-2-030 exhibiting IC50values of 202 ± 27 nM and 489 ± 83 nM, respectively. To investigate the ability of ZH-2-029 to target ABAD in living cells, HEK293T cells overexpressing ABAD were treated with ZH-2-029 followed by protein labeled with AHL-PuP-2. The results indicated that ZH-2-029 exhibited promising activity against ABAD in living cells, with an IC5025 of 2.0 ± 1.2 µM, while control compound ZH-5-057 showed an IC50greater than 25 µM. The docking study revealed that ZH-2-029 could form hydrogen bonds with Tyr168, Ser155, and Phe201 of ABAD (see e.g., Accession No. NP_004484.1 of the GENBANK® biosequence database). Notably, the binding site is positioned near the interaction surface of ABAD and Aβ, suggesting that ZH-2-029 may disrupt the ABAD-Aβ interaction. The pull-down assay demonstrated 30 that ABAD-Aβ interaction was inhibited by ZH-2-029. To further confirm the binding site of ZH-2-029 in living cells, we performed SuPUR TMT- ABPP using AHL-PuP-2 in HEK293T proteome. Unenriched proteomics data showed no significant alterations in the ABAD protein profile between the compound-treated group and DMSO group. In contrast, the enriched proteomics analysis of probe modified peptides demonstrated that ZH-2-029 35 selectively binds to the Tyr168 site at 10 µM. Thus, while not wishing to be bound by any particular theory of operation, the presently disclosed data suggest a mechanism by which Tyr168 serves as a - 92 - Attorney Docket No.: 3436 / 3 PCT ligandable site for ABAD inhibition by SuPUR ligands and an underlying mechanism of action (MoA) that presents a potential therapeutic strategy for neurodegenerative diseases. EXAMPLE 8 Discovery of First-in-class ACAT2 binders by Covalent Targeting of Tyrosine 5 To explore the disease categories overrepresented in AHL-PuP-2 labeled protein database, disease ontology (DO) enrichment analysis was performed. The analysis revealed a significant association of proteins with cell proliferation, especially for gastrointestinal (GI) cancer and squamous cell carcinoma (SCC). The phenotype screening of the presently disclosed sulfonyl purine (SuPUR) library and control compounds was performed using cell viability assay at a concentration of 30 µM. 10 Several SuPUR ligands exhibited an inhibition rate greater than 60% in SiHa cells, including ZH-2- 025, ZH-2-053, ZH-2-077, and ZH-2-101. Subsequently, IC50values of these promising compounds were assayed in SiHa cells, with ZH- 2-077 exhibiting more potent activity than ZH-2-025, ZH-2-053, and ZH-2-101. To investigate the contribution of purine core to the effect of ZH-2-077 on cell proliferation, 15 control compounds ZH-5-049-1, ZH-5-049-2, and ZH-5-051 were synthesized by applying a nitrogen walk along the purine scaffold. The cell viability results showed that ZH-2-077 maintained potent inhibitory activity in SiHa and NCI-N87 cancer cells, with IC50values of 14.5 ± 0.2 µM and 12.4 ± 2.8 µM, respectively. In contrast, no significant inhibitory activity was observed in the non-cancerous HEK293T cell line. It’s noteworthy that control compounds ZH-5-049-1, ZH-5-051, and ZH-5-049-2 20 exhibited no inhibitory activity across various cancer cell lines, suggesting that the purine core is essential for the inhibition of cancer cell proliferation. Consequently, SuPUR TMT-ABPP was performed to investigate the target and bind site of ZH- 2-077 in SiHa cells using AHL-PuP-2, with ZH-5-049-1 included as a control. The enriched proteomics result revealed that ZH-2-077 selectively and covalently binds to Tyr237 of acetyl-CoA 25 acetyltransferase 2 (ACAT2 (see e.g., Accession No. NP_005882.2 of the GENBANK® biosequence database), a key enzyme involved in fatty acid and ketone body metabolism. Meanwhile, unenriched proteomics data showed no significant alterations in the ACAT2 protein profile between the compound- treated group and DMSO group. Bioinformatics analyses of clinical profiles indicated that ACTA2 is highly expressed in certain 30 cancers and is closely associated with poor overall survival (OS), particularly in squamous and gastric cancers. Thus, whether compound ZH-2-077 might inhibit growth of cancer cells by targeting ACAT2 was tested. To further validate the target and binding site, SuPUR TMT-ABPP was performed in the SH-SY5Y neuroblastoma cell line in which ACAT2 is highly expressed. The result demonstrated that ZH-2-077 could selectively bind to ACAT2 by covalently targeting Tyr237. Gel-based competitive 35 ABPP in HEK293T soluble proteome revealed that ZH-2-077 exhibited potent activity with an IC50of 1197 ± 246 nM, while the controls showed no binding activity for ACAT2. - 93 - Attorney Docket No.: 3436 / 3 PCT Further analysis in HEK293T membrane proteome revealed that ACAT2 is primarily localized in soluble fraction. TMT-ABPP was then performed in the HEK293T soluble proteome, confirming that ZH-2-077 selectively binds to ACTA2 by targeting Tyr237 (see Accession No. Q9BWD1 of the GENBANK® biosequence database). To investigate the binding affinity in living cells, gel-based 5 ABPP was performed with HEK293T overexpressing ACAT2 by pre-treating with ZH-2-077 and control compounds. ZH-2-077 exhibited a single digital micromolar IC50of 4.2 ± 2.0 µM To investigate the impact of SuPUR regio-isomers on ACAT2 binding affinity, the 9-positioned (N9) sulfonyl purine, ZH-2-078, was synthesized. Gel-ABPP revealed ZH-2-078 completely lost activity against ACAT2. Crystallographic analysis revealed that the binding site Tyr237 is in the CoA 10 substrate pocket, where it can form an alkyl-π interaction with CoA, suggesting that Tyr237 is a crucial functional residue for ACAT2 catalytic activity. Docking studies of ACAT2 with ZH-2-077 indicated that a hydrogen bond could form between purine core of ZH-2-077 and Ile254. In contrast, ZH-2-078 was unable to retain this key interaction, resulting in a decreased binding affinity for ACAT2. Alignment of the substrate CoA with ZH-2-077 demonstrated that ZH-2-077 effectively occupies the 15 substrate CoA binding pocket 1, thereby inhibiting ACAT2 activity. Summarily, SuPUR ligand ZH-2-077 was identified as a first-in-class covalent inhibitor of ACAT2 by selectively targeting Tyr237. ZH-2-077 further exhibited promising inhibitory activity in SiHa and NCI-N87 cancer cells, supporting its use as a lead compound for inhibiting ACAT2 and designing other ACAT2 inhibitors for cancer therapeutics. 20 Discussion of the EXAMPLES One class of abundant and structurally related metabolites with divergent cell biological functions are purines. Substituted purines form the building blocks of energy cofactors (adenosine triphosphate [ATP] and guanosine triphosphate [GTP], coenzymes in oxidation-reduction reactions, secondary messengers (e.g., cyclic AMP, cyclic GMP), neurotransmitters (e.g., adenine), enzyme 25 cofactors (e.g., nicotinamide adenine dinucleotide and flavin adenine dinucleotide), inflammatory signals (e.g., urate), and nucleotides (e.g., adenosine monophosphate [AMP] and guanosine monophosphate [GMP]). These purine metabolites are generated from both de novo biosynthesis and salvage pathways. The strategic placement of a sulfonyl-purine electrophile at the N7 (AHL-PuP-2) or N9 (ZH-2- 30 087) position facilitates evaluation of regioselective binding. This approach is analogous to incorporating chirality into chemoproteomic probes for evaluating stereoselective binding, which helps identify binding events due to recognition compared with general labeling of residues. Regioselective binding by chemoproteomics, in contrast, is largely unexplored and is a distinct feature enabled by purine-based electrophiles. - 94 - Attorney Docket No.: 3436 / 3 PCT It will be understood that various details of the presently disclosed subject matter can be changed without departing from the scope of the presently disclosed subject matter. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation. - 95 -

Claims

1. Attorney Docket No.: 3436 / 3 PCT CLAIMS What is claimed is:

1. A compound having a structure of Formula (I): 5 wherein: each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; 10 X1and X2are independently selected from the group consisting of H, O, F, Cl, Br,- NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen- protecting group; X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and 15 X4is R; and R is selected from -S(=O)2-R1and -CH2-S(=O)2-R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or 20 a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein R is -S(=O)2-R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, optionally wherein R1is selected from phenyl and substituted phenyl; or 25 a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound of Formula (I) has a structure of Formula (II): - 96 - Attorney Docket No.: 3436 / 3 PCT wherein: Z is CH or N; Y is CH or N; 5 X1and X2are independently selected from the group consisting of H, F, Cl, Br, -NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group; and R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, 10 substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein Z and Y are each N, and the compound of Formula (II) has a structure of Formula (II’): 15 (Formula II’), wherein: X1and X2are independently selected from the group consisting of -H, -NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)-H, -C(=O)-alkyl, and a nitrogen-protecting group, 20 optionally where X1and X2are each H; and R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3, wherein R1is phenyl or substituted phenyl, and the compound of 25 Formula (II) has a structure of Formula (III): - 97 - Attorney Docket No.: 3436 / 3 PCT (Formula III), wherein: Z is CH or N; Y is CH or N; 5 X1and X2are independently selected from the group consisting of H, F, Cl, Br, -NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)-H, -C(=O)-alkyl, and a nitrogen-protecting group; R2, R3, R4, R5, and R6are independently selected from the group consisting of H, cyano, halo, alkyl, perhaloalkyl, alkoxy, perhaloalkoxy, carboxyl, formyl, -C(=O)-R7, 10 -NH-C(=O)-R7, and -C(=O)-N(R8)2; R7is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl; and each R8is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, and substituted aralkyl; or 15 where two R8groups together with the nitrogen to which they are attached form a substituted or unsubstituted nitrogen-containing heterocyclic ring; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein Z and Y are N, and the compound of Formula (III) has a structure of Formula (III’): 20 (Formula III’), - 98 - Attorney Docket No.: 3436 / 3 PCT wherein: X1and X2are independently selected from the group consisting of H, -NH2, F, Cl, Br, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen-protecting group, 5 optionally wherein X1and X2are each H; R2, R3, R4, R5, and R6are independently selected from the group consisting of H, cyano, halo, alkyl, perhaloalkyl, alkoxy, perhaloalkoxy, carboxyl, formyl, -C(=O)-R7, -NH-C(=O)-R7, and -C(=O)-N(R8)2; R7is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aralkyl, 10 substituted aralkyl, aryl, and substituted aryl; and each R8is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, and substituted aralkyl; or where two R8groups together with the nitrogen to which they are attached form a substituted or unsubstituted nitrogen-containing heterocyclic ring; or 15 a pharmaceutically acceptable salt thereof.

7. The compound of claim 5 or claim 6, wherein R2, R3, R4, R5, and R6are independently selected from the group consisting of H, cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, trifluoroalkoxy, methoxy, carboxyl, formyl, acetyl, -NH-C(=O)-alkyl, -C(=O)-NHR8, and , 20 wherein: R8is selected from terminal alkyne-substituted alkyl, cycloalkyl, cycloalkyl-substituted alkyl, aralkyl, and aryl; and R9is aralkyl.

8. The compound of any one of claims 5-7, wherein one or both of R2and R6are selected from 25 the group consisting of fluoro, chloro, bromo, methyl, perfluoromethyl, methoxy, and perfluoromethoxy.

9. The compound of any one of claims 5-7, wherein R4is cyano.

10. The compound of claim 1, wherein R is selected from the group consisting of: - 99 - Attorney Docket No.: 3436 / 3 PCT - 100 - Attorney Docket No.: 3436 / 3 PCT , - 101 - Attorney Docket No.: 3436 / 3 PCT - 102 - Attorney Docket No.: 3436 / 3 PCT 5 11. The compound of claim 10, wherein Z and Y are each N, and X1and X2are each H.

12. A pharmaceutical composition comprising a compound of any one of claims 1-11 and a pharmaceutically acceptable carrier.

13. A method of covalently modifying a peptide or protein, the method comprising contacting a sample comprising the peptide or protein with a compound of any one of claims 1-11 or a 10 pharmaceutical composition of claim 12.

14. The method of claim 13, wherein the contacting provides a covalent modified peptide or protein, wherein said covalently modified peptide or protein comprises one or more covalently modified tyrosine or covalently modified lysine residues, wherein the covalently modified tyrosine or covalently modified lysine residues comprise a structure: - 103 - Attorney Docket No.: 3436 / 3 PCT wherein R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, 5 and substituted heteroaryl, optionally wherein R1is selected from phenyl and substituted phenyl.

15. The method of claim 13 or claim 14, wherein covalently modifying the peptide or protein modulates one or more biological activity of said peptide or protein.

16. The method of any one of claims 13-15, wherein the peptide or protein is selected from the 10 group consisting of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD), guanine nucleotide binding protein alpha stimulating activity polypeptide (GNAS), alpha / beta- hydrolase domain 10 (ABHD10), glutathione S-transferase pi 1 (GSTP1), glucosamine- phosphate N-acetyltransferase 1 (GNPNAT1), poly(ADP-ribose) polymerase 2 (PARP2), and acetyl-CoA acetyltransferase 2 (ACAT2). 15 17. The method of any one of claims 13-16, wherein the sample comprising the peptide or protein is selected from the group consisting of a biological fluid, a cell extract, a cell, a tissue, an organ, and an organism.

18. A method of inhibiting a biological activity of a polypeptide selected from the group consisting of amyloid-beta (A^)-binding alcohol dehydrogenase (ABAD), guanine nucleotide binding 20 protein alpha stimulating activity polypeptide (GNAS), alpha / beta-hydrolase domain 10 (ABHD10), glutathione S-transferase pi 1 (GSTP1), glucosamine-phosphate N- acetyltransferase 1 (GNPNAT1), poly(ADP-ribose) polymerase 2 (PARP2), and acetyl-CoA acetyltransferase 2 (ACAT2), the method comprising contacting a sample comprising ABAD with a compound of Formula (I), thereby covalently modifying one or more amino acid residues 25 of the ABAD, GNAS, ABHD10, GSTP1, GNPNAT1, PARP2, or ACAT2 polypeptide, wherein the compound of Formula (I) has a structure: - 104 - Attorney Docket No.: 3436 / 3 PCT wherein: each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; 5 Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group consisting of H, O, F, Cl, Br,- NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen- 10 protecting group; and X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R, and R is -S(=O)2-R1, where R1is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or 15 a pharmaceutically acceptable salt thereof; optionally wherein Z and Y are each selected from N and NH.

19. The method of claim 18, wherein R is selected from the group consisting of:20 - 105 - Attorney Docket No.: 3436 / 3 PCT 20. The method of claim 19, wherein R is selected from the group consisting of:

21. The method of any one of claims 18-20, wherein: (i) the covalently modified ABAD polypeptide comprises a covalently modified non- 5 catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is tyrosine 168 (Tyr168); . (i) the covalently modified ABHD10 polypeptide comprises a covalently modified non- catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is tyrosine 215 (Tyr215); . 10 (i) the covalently modified GSTP1 polypeptide comprises a covalently modified non- catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is tyrosine 8 (Tyr8); . (i) the covalently modified GNPNAT1 polypeptide comprises a covalently modified non- catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic 15 tyrosine residue is tyrosine 165 (Tyr165); . (i) the covalently modified PARP2 polypeptide comprises a covalently modified non- catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is tyrosine 455 (Tyr455); . (i) the covalently modified ACAT2 polypeptide comprises a covalently modified non- 20 catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is tyrosine 237 (Tyr237); or. (i) the covalently modified GNAS polypeptide comprises a covalently modified non- catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is tyrosine 961 (Tyr961). 25 22. The method of any one of claims 18-21, wherein the covalently modified ABAD, GNAS, ABHD10, GSTP1, GNPNAT1, PARP2, or ACAT2 polypeptide exhibits reduced catalytic activity compared to a corresponding unmodified ABAD, GNAS, ABHD10, GSTP1, GNPNAT1, PARP2, or ACAT2 polypeptide.

23. The method of any one of claims 18-21, wherein the covalently modified ABAD polypeptide 30 exhibits decreased binding for beta-amyloid (A^) compared to a corresponding unmodified ABAD. - 106 - Attorney Docket No.: 3436 / 3 PCT 24. The method of any one of claims 18-21, wherein the covalently modified ABAD polypeptide exhibits a reduction in reactive oxygen species (ROS) induced by beta-amyloid (A^) compared to a corresponding unmodified ABAD.

25. A method of inhibiting alpha / beta-hydrolase domain 10 (ABHD10) polypeptide, the method 5 comprising contacting a sample comprising an ABHD10 polypeptide with a compound of Formula (I), thereby covalently modifying one or more amino acid residues in the ABHD10 polypeptide, wherein the compound has a structure of Formula (I): wherein: 10 each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; Y is selected from CH, N, and NH; X1and X2are independently selected from the group consisting of H, O, F, Cl, Br,- 15 NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen- protecting group; and X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R, and R is -S(=O)2-R1, where R1is selected from the group consisting of 20 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aralkyl, substituted aralkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or a pharmaceutically acceptable salt thereof; optionally wherein Y and Z are each selected from N and NH.

26. The method of claim 25, wherein R is selected from the group consisting of:25 - 107 - Attorney Docket No.: 3436 / 3 PCT 27. 5 28. The method of any one of claims 25-27, wherein the covalently modified ABHD10 polypeptide comprises a covalently modified non-catalytic tyrosine residue, optionally wherein said covalently modified non-catalytic tyrosine residue is tyrosine 215 (Tyr215).

29. The method of any one of claims 25-27, wherein the covalently modified ABHD10 polypeptide exhibits reduced catalytic activity compared to a corresponding unmodified ABHD10. 10 30. A method of identifying a reactive amino acid residue of a protein, optionally wherein the reactive amino acid residue is a tyrosine residue or a lysine residue, the method comprising: (a) providing a protein sample comprising isolated proteins, living cells, or a cell lysate; (b) contacting the protein sample with a probe compound for a period of time sufficient for the probe compound to covalently react with at least one reactive amino acid residue 15 in the protein sample, thereby forming at least one modified reactive amino acid residue; and (c) analyzing proteins in the protein sample to identify at least one modified reactive amino acid residue, thereby identifying at least one reactive amino acid residue of a protein; wherein the probe compound has a structure of Formula (I): 20 - 108 - Attorney Docket No.: 3436 / 3 PCT wherein: each represents a single or double bond; subject to the proviso that three represent a double bond and no two adjacent are both double bonds; Z is selected from CH, N, and NH; 5 Y is selected from CH, N, and NH; X1and X2are independently selected from the group consisting of H, O, F, Cl, Br,- NH2, -NHX5, and -N(X5)2, wherein each X5is selected from the group consisting of alkyl, aralkyl, aryl, -C(=O)H, -C(=O)-alkyl, and a nitrogen- protecting group; 10 X3and X4are selected from H and R, wherein one of X3and X4is H and one of X3and X4is R, and R is selected from -S(=O)2-R1, where R1is selected from the group consisting of substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl and substituted heteroaryl, wherein said substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl or substituted 15 heteroaryl comprises at least one substituent comprising a terminal alkyne moiety, a fluorophore, or a detectable tag; and wherein the at least one modified reactive amino acid residue comprises a structure - S(=O)2-R1.

31. The method of claim 30, wherein Y and Z are each selected from N and NH. 20 - 109 -

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