Covalent Modifiers
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Sunday, September 13, 2026
Isoform-Selective Targeting of Akt Through Covalent Allosteric Inhibition
Monday, August 31, 2026
An enantioselective covalent inhibitor of BAX confers cytoprotection in vivo
Peiwen Shi, Bruno Melillo, Matthew W. McHenry, Christina M. Camara, Ka Yang, Evert Njomen, Marina Godes, Maria F. Pazyra-Murphy, Mary Rose Branch, Bethany Tesar, Rosalind A. Segal, Lee L. Rubin, Michael D. Cameron, Gregory H. Bird, Thomas E. Wales, Steven P. Gygi, Benjamin F. Cravatt, and Loren D. Walensky.
Nat Chem Biol (2026).
https://doi.org/10.1038/s41589-026-02297-9
No therapies directly block apoptosis in tissue injury or the many diseases driven by cell loss. The BCL-2 family protein BAX is a central mediator of this pathway and C126 resides within a key regulatory region where physiologic or pharmacologic ligands can activate or inhibit its function. Here, we report enantioselective covalent BAX inhibitors that site-specifically react with C126 and confer cytoprotection across multiple cell types. These ligands constrain BAX conformation and suppress apoptosis in a strictly BAX-dependent manner. Medicinal chemistry optimization yielded covalent BAX inhibitor 3 (CBI-3), an analog with pharmacokinetics suitable for in vivo studies. In a murine model of Fas-induced fulminant hepatic failure, CBI-3 reduced hepatocyte apoptosis and preserved liver histology and survival. CBI-3 also conferred cytoprotection of motor neurons derived from human induced pluripotent stem cells of healthy and amyotrophic lateral sclerosis donors. These findings establish covalent BAX inhibition as a therapeutic strategy to directly block pathologic cell death.
Sunday, August 30, 2026
Enhancing De Novo Designed Peptides and Proteins via Irreversible Covalent Isoquinolinium Capture
Paul M. Levine, Patrick W. Erickson, Timothy W. Craven, Aaron T. Balana, Derrick R. Hicks, Green Ahn, Chan J. Kim, Lisa S. Brandenburg, Wei Yang, Danielle P. Johnson Erickson,
ACS Chem. Biol. (2026)
Sulfonyl-Imidazopyridines Decouple Reactivity from Stability for Ligandability Mapping and Covalent Inhibitor Discovery
Zhihong Li; Madeleine L. Ware; Phillip W. Gingrich; Bissan Al-Lazikani; Ku-Lung Hsu *
Tuesday, August 25, 2026
Development of Covalent Inhibitors of Chikungunya Virus nsP2 Cysteine Protease Enabled by Direct-to-Biology Synthesis and Screening D
Zhengjun Cai § ; Kan Li § ; Sainetra Sridhar; Haozhou Tan; Hiwot Demssie; Gaungjin Fan; Wenyi Zhang; Bobby Brooke Herrera; Jun Wang
J. Med. Chem. (2026)
https://doi.org/10.1021/acs.jmedchem.5c03672
Chikungunya virus (CHIKV), an arthropod-borne alphavirus, has emerged as a global health threat due to its rapid transmission and the lack of effective antiviral therapies. The cysteine protease activity of the virus-encoded nonstructural protein 2 (nsP2) is critical for CHIKV replication, as it processes viral polyproteins and counteracts host antiviral defenses, establishing it as a highly attractive target for therapeutic intervention. In this study, we present a rapid drug development platform that integrates covalent docking with direct-to-biology (D2B) synthesis and screening to identify nsP2 inhibitors. Candidates prioritized by in silico docking were synthesized and directly tested in FRET enzymatic assays without purification. This approach led to the identification of several nsP2 inhibitors with diverse chemical scaffolds, potent enzymatic inhibition, and antiviral activity. Together, these findings establish a streamlined strategy for covalent inhibitor development and provide promising leads for CHIKV antiviral development.
Sunday, August 23, 2026
Covalent allosteric inhibition of AARS1 lactyltransferase
Yunyuan Huang, Siying Liu, Luyang Tian, Yang Tang, Yilin Dou, Huiling Wang, Tao Zheng, Mingyang Wang, Runhao Li, Zhi Wang, Zhaocai Zhou, Xin Chen & Jinrong Min
Nature Communications (2026)
https://doi.org/10.1038/s41467-026-76732-9
Alanyl-tRNA synthetase 1 (AARS1) was recently identified as a lactyltransferase responsible for protein lactylation, a modification associated with epigenetic regulation and metabolic adaptation. Here, we report compound XY353, which covalently binds C184 of AARS1, inducing steric clashes with F175 and triggering structural rearrangements in the region that displace W176, a key residue for lactate binding. By means of a combination of a variety of biophysical and enzymatic assays with MD simulations and structural analysis, we show that XY353 and its derivative XY353-1 inhibit AARS1 by competing with lactate via the C184–F175–W176 relay, supporting a covalent allosteric mechanism of inhibition, which is further confirmed by our cellular data that XY353-1 reduces lactylation of the AARS1 substrate YAP and suppresses the proliferation of HGC-27 cells. Collectively, these findings identify a covalent allosteric mechanism for AARS1 inhibition and provide chemical tools to explore its biological functions.
Saturday, August 22, 2026
Sulfonyl-Imidazopyridines Decouple Reactivity from Stability for Ligandability Mapping and Covalent Inhibitor Discovery
Zhihong Li; Madeleine L. Ware; Phillip W. Gingrich; Bissan Al-Lazikani; Ku-Lung Hsu *
Journal American Chemical Society (2026)
https://doi.org/10.1021/jacs.6c07487
Isoform-Selective Targeting of Akt Through Covalent Allosteric Inhibition
'Angelo, Giovanni Danilo; Pervanidis, Kosmas Alexandros; Athanasiadis, Ioannis; Lukianchikov, Vladimir; Scrima, Andrea; Depta, Laura; St...
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Xu-liang Xu, Ti-ti Ying, Xiao-wen Wu, Yun-jun Chen, Gang-ao Hu, Yu-tian Guan, Shi-yi Liu, He Wang, Mohamed Seif, Mahmoud Emam, Hong Wang, We...
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Joseph E Klebba, Nilotpal Roy, Steffen M Bernard, Stephanie Grabow, Melissa A. Hoffman, Hui Miao, Junko Tamiya, Jinwei Wang, Cynthia Berry, ...
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Lavleen K. Mader, Namita Maunick, Jessica E. Borean, Jeffrey W. Keillor RSC Med. Chem. , 2025 https://doi.org/10.1039/D5MD00777A Human tissu...