tetano
Editor, Senior Moderator
Acta Pharm Sin B
. 2026 Oct;16(10):6799-6813.
doi: 10.1016/j.apsb.2026.03.008. Epub 2026 Mar 10.
Qian Guo 1 , Xiaomeng Yang 1 , Zhihao Zhao 2 , Jian-Piao Cai 1 , Liang Wei 1 , Kaiming Tang 1 3 , Wan-Mui Chan 1 3 , Allen Wing-Ho Chu 1 3 , Yixin Huang 4 , Tong-Yun Wang 5 , Yubin Xie 1 , Yulan Liu 2 , Zi-Wei Ye 4 , Tao Ni 4 , Hin Chu 1 3 6 , Jasper Fuk-Woo Chan 1 3 6 , Kelvin Kai-Wang To 1 3 6 , Kwok-Yung Yuen 1 3 6 , Ying-Chih Chiang 2 , Shuofeng Yuan 1 3 6
Affiliations Expand
The viral RNA-dependent RNA polymerase (RdRp) is a conserved and compelling target for pan-coronavirus antiviral development. To date, all US Food and Drug Administration (FDA)-approved RdRp inhibitors are nucleotide inhibitors (NIs), which are prone to drug resistance and show limited clinical efficacy. Developing alternative non-nucleotide inhibitors (NNIs) with high target specificity, structural diversity, and metabolic stability could yield more effective antivirals. Here, we identify an allosteric RdRp NNI, BAY-850, via computational screening. BAY-850 exhibits potent, broad-spectrum antiviral activity against multiple SARS-CoV-2 variants and other human coronaviruses. Mechanistic studies show that BAY-850 binds directly to a previously unrecognized allosteric site on nsp12, thereby fine-tuning the catalytic motif F loop out-conformation the orthosteric site. Importantly, therapeutic administration of BAY-850 significantly reduces viral loads in the nasal turbinates and lungs of SARS-CoV-2-infected K18-hACE2 mice. These findings validate a novel allosteric site in RdRp and support BAY-850 as a start-point for broad-spectrum anti-coronavirus development.
Keywords: Allosteric-site inhibitor; Animal model; Drug-resistance; Non-nucleotide inhibitor; Pan-coronavirus; RdRp; Reverse genetics; SARS-CoV-2.
. 2026 Oct;16(10):6799-6813.
doi: 10.1016/j.apsb.2026.03.008. Epub 2026 Mar 10.
Identification and characterization of a non-nucleotide RdRp allosteric inhibitor with pan-coronavirus protection
Qian Guo 1 , Xiaomeng Yang 1 , Zhihao Zhao 2 , Jian-Piao Cai 1 , Liang Wei 1 , Kaiming Tang 1 3 , Wan-Mui Chan 1 3 , Allen Wing-Ho Chu 1 3 , Yixin Huang 4 , Tong-Yun Wang 5 , Yubin Xie 1 , Yulan Liu 2 , Zi-Wei Ye 4 , Tao Ni 4 , Hin Chu 1 3 6 , Jasper Fuk-Woo Chan 1 3 6 , Kelvin Kai-Wang To 1 3 6 , Kwok-Yung Yuen 1 3 6 , Ying-Chih Chiang 2 , Shuofeng Yuan 1 3 6
Affiliations Expand
- PMID: 42948681
- PMCID: PMC13712280
- DOI: 10.1016/j.apsb.2026.03.008
Abstract
The viral RNA-dependent RNA polymerase (RdRp) is a conserved and compelling target for pan-coronavirus antiviral development. To date, all US Food and Drug Administration (FDA)-approved RdRp inhibitors are nucleotide inhibitors (NIs), which are prone to drug resistance and show limited clinical efficacy. Developing alternative non-nucleotide inhibitors (NNIs) with high target specificity, structural diversity, and metabolic stability could yield more effective antivirals. Here, we identify an allosteric RdRp NNI, BAY-850, via computational screening. BAY-850 exhibits potent, broad-spectrum antiviral activity against multiple SARS-CoV-2 variants and other human coronaviruses. Mechanistic studies show that BAY-850 binds directly to a previously unrecognized allosteric site on nsp12, thereby fine-tuning the catalytic motif F loop out-conformation the orthosteric site. Importantly, therapeutic administration of BAY-850 significantly reduces viral loads in the nasal turbinates and lungs of SARS-CoV-2-infected K18-hACE2 mice. These findings validate a novel allosteric site in RdRp and support BAY-850 as a start-point for broad-spectrum anti-coronavirus development.
Keywords: Allosteric-site inhibitor; Animal model; Drug-resistance; Non-nucleotide inhibitor; Pan-coronavirus; RdRp; Reverse genetics; SARS-CoV-2.