Development of GS-441524 Derivatives as Potent SARS-CoV-2 Mac1 Inhibitors via a Direct-to-Biology Approach

Peng, K.; Chakraborty, S.; Wallace, S. D.; Noll, J. C. G.; Shang, J.; Lu, X.; Choi, A.; Whittaker, G.; Fromme, J. C.; Lin, H.

doi:10.64898/2026.06.24.734322

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bioRxiv · 10.64898/2026.06.24.734322

Development of GS-441524 Derivatives as Potent SARS-CoV-2 Mac1 Inhibitors via a Direct-to-Biology Approach

Peng, K.·Chakraborty, S.·Wallace, S. D.·Noll, J. C. G.·Shang, J.·Lu, X.·Choi, A.·Whittaker, G.·Fromme, J. C.·Lin, H.

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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 M 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.

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Peng, K., Chakraborty, S., Wallace, S. D., Noll, J. C. G., Shang, J., Lu, X., Choi, A., Whittaker, G., Fromme, J. C., Lin, H.. 2026-06-25. Development of GS-441524 Derivatives as Potent SARS-CoV-2 Mac1 Inhibitors via a Direct-to-Biology Approach. https://doi.org/10.64898/2026.06.24.734322

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