cysteine targeting

K777 is a potent, orally active, and irreversible inhibitor of cysteine protease, functioning as a potent CYP3A4 inhibitor (IC50 = 60 nM) and a selective CCR4 antagonist, which inhibits chemotaxis. K777 irreversibly inhibits Cruzain, the major cysteine protease of Trypanosoma cruzi, and cathepsins B and L, targeting cathepsin-mediated cell entry and exhibiting broad-spectrum antiviral activity. It inhibits EBOV and SARS-CoV pseudovirus entry with IC50 values of 0.87 nM and 0.68 nM, respectively.

MS8511 HCl is a selective and potent covalent inhibitor of G9a GLP that acts by targeting cysteine residues in the substrate binding site. MS8511 has anticancer activity and antiproliferative activity and reduces intracellular H3K9me2 levels.MS8511 can be used to study a wide range of cancers including brain, breast, and ovarian cancers .

Helenalin is a selective inhibitor of transcription factor NF-κB by direct targeting of p65. It is an anti-inflammatory sesquiterpene lactone compound with alkylating activity. Through its ability to target the cysteine sulfhydryl groups in the p65 subunit of NF-κB, helenalin effectively inhibits its DNA binding.

4-Chloropyridine acts as an inhibitor of Nicotinamide N-methyltransferase (NNMT). Serving as a substrate for NNMT, this compound enhances the electrophilicity at the C4 position through methylation of the pyridine nitrogen. This modification facilitates an aromatic nucleophilic substitution reaction with the non-catalytic cysteine (C159) in NNMT, ultimately leading to suicidal activity inhibition of the enzyme. 4-Chloropyridine is a promising candidate for the development of activity-based probes targeting NNMT functions.

RA-0002034 is a potent, irreversible covalent inhibitor specifically targeting the alphavirus nsP2 cysteine protease, exhibiting broad-spectrum antiviral activity [IC50 = 60 nM].

AC1115 is a potent and selective next-generation antiviral compound targeting SARS-CoV-2 Mpro and the host lysosomal cysteine protease cathepsin L (CTSL), demonstrating high antiviral activity.

MS8511 (hydrochloride) is a specific covalent and irreversible inhibitor of G9a GLP, targeting the cysteine residue at the substrate binding site. It has an IC50 of 100 nM for G9a and 140 nM for GLP, with Kd values of 44 nM for G9a and 46 nM for GLP. This compound reduces intracellular H3K9me2 levels and enhances antiproliferative activity, making it useful for studying various cancers, including brain, breast, ovarian, lung, bladder cancers, melanoma, and colorectal cancer, as well as other diseases like Alzheimer's disease (AD), sickle cell disease, and Prader-Willi syndrome (PWS).

β-Glucuronidase-IN-3 (Compound 49) is a covalent allosteric inhibitor targeting β-glucuronidase. It exhibits potent inhibitory activity against Escherichia coli β-glucuronidase (EcGUS) with an IC50 of 12.9 nM. The compound exerts its inhibitory effect through reversible covalent modification of cysteine residues (Cys28, Cys443, and Cys197) on EcGUS. It is applicable in research on gut microbiota-related diseases, particularly in reducing the toxic side effects of Irinotecan and non-steroidal anti-inflammatory drugs (NSAIDs).

FGA139 is an inhibitor of cysteine proteases, specifically targeting cathepsin B and L with IC50 values of 4.98 μM and 3.14 μM, respectively. It reduces the production of NO in LPS-induced RAW264.7 cells and lowers TNFα levels in microglia, demonstrating antioxidant and anti-inflammatory properties. Additionally, FGA139 enhances the secretion of neuroprotective metabolites such as purines and linoleic acid in LPS-stimulated microglia. This compound is applicable in the study of neuroinflammatory diseases.

DCG04 is a multivalent ligand for the mannose-6-phosphate receptor. DCG-04 is an activity-based probe for cysteine cathepsins, enabled fluorescent readout of its receptor-targeting properties. DCG04 is used for endolysosomal targeting of an activity-based

AP-22161 selectively binds the Src SH2 domain by targeting highly conserved phosphotyrosine binding to cysteine residues in the pocket. AP-22161 selectively inhibits Src SH2 binding and can be used to inhibit osteoclast absorption.

Palmitic acid-13C is intended for use as an internal standard for the quantification of palmitic acid by GC- or LC-MS. Palmitic acid is a 16-carbon saturated fatty acid. It comprises approximately 25% of human total plasma lipids.1 It increases protein levels of COX-2 in RAW 264.7 cells when used at a concentration of 75 μM.2 Palmitic acid is involved in the acylation of proteins to anchor membrane-bound proteins to the lipid bilayer.2,3,4,5,6 |1. Santos, M.J., López-Jurado, M., Llopis, J., et al. Influence of dietary supplementation with fish oil on plasma fatty acid composition in coronary heart disease patients. Ann. Nutr. Metab. 39(1), 52-62 (1995).|2. Lee, J.Y., Sohn, K.H., Rhee, S.H., et al. Saturated fatty acids, but not unsaturated fatty acids, induced the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J. Biol. Chem. 276(20), 16683-16689 (2001).|3. Dietzen, D.J., Hastings, W.R., and Lublin, D.M. Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J. Biol. Chem. 270(12), 6838-6842 (1995).|4. Robinson, L.J., and Michel, T. Mutagenesis of palmitoylation sites in endothelial nitric oxide synthase identifies a novel motif for dual acylation and subcellular targeting. Proc. Nat. Acad. Sci. USA 92(25), 11776-11780 (1995).|5. Topinka, J.R., and Bredt, D.S. N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Neuron 20(1), 125-134 (1998).|6. Miggin, S.M., Lawler, O.A., and Kinsella, B.T. Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation. J. Biol. Chem. 278(9), 6947-6958 (2003).

Palmitic acid-13C is intended for use as an internal standard for the quantification of palmitic acid by GC- or LC-MS. Palmitic acid-13C contains 13C at the C2 position and has been used in the study of free fatty acid incorporation into phospholipid fatty acids in soil microbes.1 Palmitic acid is a 16-carbon saturated fatty acid. It comprises approximately 25% of human total plasma lipids.2 It increases protein levels of COX-2 in RAW 264.7 cells when used at a concentration of 75 μM.3 Palmitic acid is involved in the acylation of proteins to anchor membrane-bound proteins to the lipid bilayer.3,4,5,6,7 |1. Dippold, M.A., and Kuzyakov, Y. Direct incorporation of fatty acids into microbial phospholipids in soils: Position-specific labeling tells the story. Geochim. Cosmochim. Acta 174(1), 211-221 (2016).|2. Santos, M.J., López-Jurado, M., Llopis, J., et al. Influence of dietary supplementation with fish oil on plasma fatty acid composition in coronary heart disease patients. Ann. Nutr. Metab. 39(1), 52-62 (1995).|3. Lee, J.Y., Sohn, K.H., Rhee, S.H., et al. Saturated fatty acids, but not unsaturated fatty acids, induced the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J. Biol. Chem. 276(20), 16683-16689 (2001).|4. Dietzen, D.J., Hastings, W.R., and Lublin, D.M. Caveolin is palmitoylated on multiple cysteine residues. Palmitoylation is not necessary for localization of caveolin to caveolae. J. Biol. Chem. 270(12), 6838-6842 (1995).|5. Robinson, L.J., and Michel, T. Mutagenesis of palmitoylation sites in endothelial nitric oxide synthase identifies a novel motif for dual acylation and subcellular targeting. Proc. Nat. Acad. Sci. USA 92(25), 11776-11780 (1995).|6. Topinka, J.R., and Bredt, D.S. N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Neuron 20(1), 125-134 (1998).|7. Miggin, S.M., Lawler, O.A., and Kinsella, B.T. Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation. J. Biol. Chem. 278(9), 6947-6958 (2003).

EN219 is a synthetic recruiter of the E3 ubiquitin ligase RNF114.1It binds to cysteine 8 (C8) in the intrinsically disordered region of RNF114 (RNF114-C8; IC50= 470 nM) and inhibits RNF114-induced autoubiquitination and p21 ubiquitination in a cell-free assay when used at a concentration of 50 μM. EN219 (1 μM) also interacts with cysteine residues in the tubulin β1 chain (TUBB1), heat shock protein 60 (Hsp60), also known as Hsp family D member 1 (HspD1), and histone H3.1 (HIST1H3A) in 231MFP human breast cancer cells in a proteomic profiling assay. It has been linked to the bromodomain and extra terminal domain (BET) inhibitor ligand (+)-JQ1 for use as a proteolysis-targeting chimera (PROTAC) to degrade bromodomain-containing protein 4 (BRD4) in 231MFP cells. 1.Luo, M., Spradlin, J.N., Boike, L., et al.Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product functionCell Chem. Biol.28(4)559-566(2021)

Hypotaurine (2-Aminoethanesulfinic acid), functioning as an intermediate in the biosynthesis of taurine from cysteine within astrocytes, acts as an endogenous inhibitory amino acid targeting the glycine receptor.

Z-L(D-Val)G-CHN2, an isoform of Z-LVG-CHN2, serves as a cell-permeable and irreversible inhibitor of cysteine proteinase. This tripeptide derivative emulates a segment of the human cysteine proteinase-binding center and demonstrates selective antiviral activity, inhibiting herpes simplex virus (HSV) yet exhibiting negligible impact on poliovirus replication. Notably, Z-LVG-CHN2 effectively impedes SARS-CoV-2 replication with an EC50 value of 190 nM by targeting the SARS-CoV-2 3CL protease [3].

Zovostotug is a monoclonal antibody (mAb) targeting the human CD163, specifically the scavenger receptor cysteine-rich (SRCR) type 1 M130 domain [1].

Z-FG-NHO-BzOME is a chemical compound that functions as a cysteine protease inhibitor, selectively targeting and inhibiting cathepsin B, cathepsin L, cathepsin S, and papain [1].

ICMT-IN-54 (compound 7c), an adamantyl analogue, serves as an ICMT inhibitor with an IC50 value of 12.4 μM, targeting the methylation process facilitated by ICMT. It specifically inhibits the methylation of BFC (N-biotinyl-(6-aminohexanoic)-S-farnesyl-L-cysteine) in Saccharomyces cerevisiae expressing ICMT, marking an indirect inhibition of ICMT-mediated methylation [1].

S7, a peptide antagonist of the IL-6 receptor, concentration-dependently inhibits IL-6 binding to its receptor. At 50 µM, S7 suppresses IL-6-triggered elevations in VEGF levels within C-33 A cervical cancer cells and RPMI-8226 B cell lymphocytes. It significantly reduces tumor volume in a C-33 A cervical cancer mouse xenograft model with IL-6 overexpression, following a dosage regimen of 50 mg/kg bi-daily. Moreover, when linked to cysteine on lipid nanoparticles (LNPs) encapsulating doxorubicin, S7 enhances glioma targeting and improves survival rates in a U251 glioblastoma mouse xenograft model.

F-amidine is a selective inhibitor of protein arginine deiminases (PADs), specifically targeting PAD1 and PAD4 with in vitro IC50 values of 29.5, 350, and 21.6 µM for PAD1, PAD3, and PAD4, respectively. It irreversibly inactivates all four PAD subtypes by covalently modifying an active site cysteine crucial for enzymatic activity, with kinact/KI values of 2,800, 380, 170, and 3,000 M^-1min^-1. Additionally, F-amidine demonstrates cytotoxicity against HL-60, MCF-7, and HT-29 cancer cell lines, with IC50s of 0.5, 0.5, and 1 μM, respectively.

2G-HaloAUTAC (Compound tt44), a second-generation autophagy-targeting chimera (2G-HaloAUTAC), enhances the activity of autophagy-targeting chimeras (AUTAC) by substituting the L-Cysteine (L-Cys) linker with alternative structures. This compound demonstrates degradative activity against EGFP-HaloTag protein through an autophagy mechanism.

Puxitatugsamrotecan (AZD8205) is an antibody-drug conjugate (ADC) targeting B7-H4. It is formed by conjugating the Puxitatug antibody, which targets B7-H4, with the Puxitatug samrotecan drug-linker through random conjugation by reducing interchain cysteine. Puxitatug samrotecan exhibits antitumor activity and can be utilized in the study of cancers expressing B7-H4.

AZD0516 is a pioneering antibody-drug conjugate (ADC) targeting Six Transmembrane Epithelial Antigen of the Prostate 2 (STEAP2). It is composed of an anti-STEAP2 monoclonal antibody (mAb) linked via a cysteine-maleimide reactive, β-glucuronidase-cleavable linker to the topoisomerase 1 inhibitor Exatecan. AZD0516 is applicable for prostate cancer research.