tetano
Editor, Senior Moderator
Eur J Med Chem
. 2026 Sep 10:320:119280.
doi: 10.1016/j.ejmech.2026.119280. Online ahead of print.
Kewen Peng 1 , Suryadeep Chakraborty 2 , Shamar D Wallace 3 , Jessica Caroline Gomes Noll 4 , Jialin Shang 5 , Xuan Lu 6 , Annette Choi 4 , Gary Whittaker 4 , J Christopher Fromme 3 , Hening Lin 7
Affiliations Expand
Targeting viral macrodomains (Mac) has emerged as a promising strategy for antiviral drug development, especially after the outbreak of COVID-19 that claimed millions of lives worldwide. Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mac1 inhibitors have been reported in the past few years. In the present work, we converted GS-441524 (IC50 of ∼10 μM for SARS-CoV-2 Mac1) to KP-S54 (18c), a potent inhibitor of both SARS-CoV-2 Mac1 (IC50: 44 nM) and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 (IC50: 91 nM) through an iterative direct-to-biology approach. This approach leverages efficient amide-coupling reaction and the mix-and-read fluorescence polarization (FP) assays where reaction mixtures could be screened directly without purification. Cocrystal structure of a selected derivative (12p) binding to SARS-CoV-2 Mac1 revealed the binding mode, which will guide future drug development against viral macrodomains.
. 2026 Sep 10:320:119280.
doi: 10.1016/j.ejmech.2026.119280. Online ahead of print.
Development of GS-441524 derivatives as potent SARS-CoV-2 Mac1 inhibitors via a direct-to-biology approach
Kewen Peng 1 , Suryadeep Chakraborty 2 , Shamar D Wallace 3 , Jessica Caroline Gomes Noll 4 , Jialin Shang 5 , Xuan Lu 6 , Annette Choi 4 , Gary Whittaker 4 , J Christopher Fromme 3 , Hening Lin 7
Affiliations Expand
- PMID: 42721552
- DOI: 10.1016/j.ejmech.2026.119280
Abstract
Targeting viral macrodomains (Mac) has emerged as a promising strategy for antiviral drug development, especially after the outbreak of COVID-19 that claimed millions of lives worldwide. Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mac1 inhibitors have been reported in the past few years. In the present work, we converted GS-441524 (IC50 of ∼10 μM for SARS-CoV-2 Mac1) to KP-S54 (18c), a potent inhibitor of both SARS-CoV-2 Mac1 (IC50: 44 nM) and Middle East respiratory syndrome coronavirus (MERS-CoV) Mac1 (IC50: 91 nM) through an iterative direct-to-biology approach. This approach leverages efficient amide-coupling reaction and the mix-and-read fluorescence polarization (FP) assays where reaction mixtures could be screened directly without purification. Cocrystal structure of a selected derivative (12p) binding to SARS-CoV-2 Mac1 revealed the binding mode, which will guide future drug development against viral macrodomains.