Highly effective viral RdRP translocation hindrance by the remdesivir nucleotide
7 affiliations
- 1State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences , Wuhan 430207 ,
- 2University of Chinese Academy of Sciences , Beijing 100049 ,
- 3State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences ; Shanghai 201203 ,
- 4Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences , Shanghai 201204 ,
- 5State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University , Tianjin 300353 ,
- 6School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences , Hangzhou 310024 ,
- 7Drug Discovery Center for Infectious Diseases, Nankai University , Tianjin 300350 ,
Abstract
Nucleoside/nucleotide analogs (NAs) typically interfere with substrate selection and catalysis steps of polymerase nucleotide addition cycle (NAC), thereby affecting polymerase catalytic efficiency. In contrast, their interference with post-chemistry translocation is rarely considered in rational design, partly due to a lack of direct and quantitative evidence for such interference. Remdesivir (RDV) is an adenosine analog with broad-spectrum antiviral activity against diverse RNA virus families and has been approved for COVID-19 treatment. RDV is capable of inducing a characteristic “delayed” intervention, wherein the interference occurs several NACs after its incorporation. By combining X-ray crystallography, quench-flow kinetics, and molecular dynamics simulations, we show that the composite rate of RDV translocation from product strand position −3 to −4 and subsequent catalysis is at least 100-fold slower than that of adenosine in an enterovirus RdRP. However, mutating the corresponding roadblock residue serine417 to glycine largely abolishes this difference. Nonetheless, the incorporated RDV nucleotide can still alter the free-energy landscape even in the S417G mutant complex, enabling the capture of an over-translocated state. Our work demonstrates translocation-related intervention as an effective and broadly applicable polymerase intervention strategy in NA rational design.
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BibTeX
@article{li2026highly,
title = {{Highly effective viral RdRP translocation hindrance by the remdesivir nucleotide}},
author = {Rui Li and Qiang Shao and Meihua Wang and Chunyan Feng and Qin Xu and Qisheng Wang and Luqing Shang and Yechun Xu and Peng Gong},
journal = {Nucleic Acids Research},
year = {2026},
month = oct,
doi = {10.1093/nar/gkag957},
url = {https://academic.oup.com/nar/article/doi/10.1093/nar/gkag957/8937189},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Highly effective viral RdRP translocation hindrance by the remdesivir nucleotide
AU - Rui Li
AU - Qiang Shao
AU - Meihua Wang
AU - Chunyan Feng
AU - Qin Xu
AU - Qisheng Wang
AU - Luqing Shang
AU - Yechun Xu
AU - Peng Gong
PY - 2026
DA - 2026/10/01
JO - Nucleic Acids Research
DO - 10.1093/nar/gkag957
UR - https://academic.oup.com/nar/article/doi/10.1093/nar/gkag957/8937189
AB - Nucleoside/nucleotide analogs (NAs) typically interfere with substrate selection and catalysis steps of polymerase nucleotide addition cycle (NAC), thereby affecting polymerase catalytic efficiency. In contrast, their interference with post-chemistry translocation is rarely considered in rational design, partly due to a lack of direct and quantitative evidence for such interference. Remdesivir (RDV) is an adenosine analog with broad-spectrum antiviral activity against diverse RNA virus families and has been approved for COVID-19 treatment. RDV is capable of inducing a characteristic “delayed” intervention, wherein the interference occurs several NACs after its incorporation. By combining X-ray crystallography, quench-flow kinetics, and molecular dynamics simulations, we show that the composite rate of RDV translocation from product strand position −3 to −4 and subsequent catalysis is at least 100-fold slower than that of adenosine in an enterovirus RdRP. However, mutating the corresponding roadblock residue serine417 to glycine largely abolishes this difference. Nonetheless, the incorporated RDV nucleotide can still alter the free-energy landscape even in the S417G mutant complex, enabling the capture of an over-translocated state. Our work demonstrates translocation-related intervention as an effective and broadly applicable polymerase intervention strategy in NA rational design.
SN - 0305-1048
SN - 1362-4962
ER -