SARS-CoV-2 Resistance to Small Molecule Inhibitors
Uxua Modrego Lopez, Md. Mehedi Hasan, Brandon Havranek, Shahidul M Islam
Current Clinical Microbiology Reports, doi:10.1007/s40588-024-00229-6
Purpose of the Review SARS-CoV-2 undergoes genetic mutations like many other viruses. Some mutations lead to the emergence of new Variants of Concern (VOCs), affecting transmissibility, illness severity, and the effectiveness of antiviral drugs. Continuous monitoring and research are crucial to comprehend variant behavior and develop effective response strategies, including identifying mutations that may affect current drug therapies. Recent Findings Antiviral therapies such as Nirmatrelvir and Ensitrelvir focus on inhibiting 3CLpro, whereas Remdesivir, Favipiravir, and Molnupiravir target nsp12, thereby reducing the viral load. However, the emergence of resistant mutations in 3CLpro and nsp12 could impact the efficiency of these small molecule drug therapeutics. Summary This manuscript summarizes mutations in 3CLpro and nsp12, which could potentially reduce the efficacy of drugs. Additionally, it encapsulates recent advancements in small molecule antivirals targeting SARS-CoV-2 viral proteins, including their potential for developing resistance against emerging variants.
Author contributions Uxua Modrego Lopez wrote the main manuscript text, Md. Mehedi Hasan edited the main manuscript text, Uxua Modrego Lopez prepared Tables 1 and 2 , Md. Mehedi Hasan prepared Figure 1 , Shahidul M. Islam wrote, edited and supervised the work, All authors reviewed the manuscript. Funding Shahidul is supported by the National Institutes of Health through RCMI (U54MD015959), COBRE (P20GM145765) and DE-INBRE (P20GM103446), and the National Science Foundation through PREM (2122158). We express our gratitude to Zymir Robinson for his initial assistance and helpful suggestions. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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'Novel Therapeutics Against Coronavirus (COVID-19) - StatPearls - NCBI '
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'SARS-CoV-2 main protease (Mpro): Structure, function, and emerging '
'therapies for COVID-19. MedComm (Beijing). 2022;3(3):e151. '
'https://doi.org/10.1002/MCO2.151.',
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{ 'key': '229_CR31',
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'K. Hilgenfeld R (2020) Crystal structure of SARS-CoV-2 main protease '
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'coronavirus main proteases. Journal of General Virology. 2002;83:595–9.',
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'doi-asserted-by': 'publisher',
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'2016;59:6595–628.',
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'SARS-CoV-2 Infection: Results of the Phase 2a Part. Antimicrob Agents '
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'Islam SM. Discovery of Nirmaltrelvir Resistance Mutations in SARS-CoV-2 '
'3CLpro: A Computational-Experimental Approach. J Chem Inf Model. 2023; '
'https://doi.org/10.1021/acs.jcim.3c01269. This study uses computational '
'and in-vitro methods to identify potential mutations in 3CLpro resistant '
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'Cent Sci. 2023; https://doi.org/10.1021/acscentsci.3c00538. This study '
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'Biochemistry. 2022; https://doi.org/10.1021/acs.biochem.2c00489. This '
'study carried out in silico and in-vitro experiments to reveal 5 '
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'of SARS-CoV-2 protease inhibitors. '
'https://doi.org/10.1101/2023.02.25.530000. This study determinated '
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'occurring 3CLpro variants associated with resistance to 3CLpro '
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'Suzuki T, Kawaoka Y. In vitro and in vivo characterization of SARS-CoV-2 '
'resistance to Entreselvir. Nat Commun. 2023; '
'https://doi.org/10.1038/s41467-023-40018-1. This study identified double '
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{ 'key': '229_CR47',
'first-page': '6499',
'volume': '2022',
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'variants. Commun Biol. 2023; https://doi.org/10.1038/s42003-023-05071-y.',
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'Hariprasad G, Hasan GM, Hassan MI. Insights into SARS-CoV-2 genome, '
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'Gorbalenya AE, Linne U, Ziebuhr J. Coronavirus replication-transcription '
'complex: Vital and selective NMPylation of a conserved site in nsp9 by '
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'https://doi.org/10.1073/PNAS.2022310118/-/DCSUPPLEMENTAL.',
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'SARS-CoV-2 RNA polymerase is a viral RNA capping enzyme. Nucleic Acids '
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'M. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent '
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{ 'key': '229_CR57',
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'2022; https://doi.org/10.1038/s41467-022-29104-y. This study identified '
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'https://doi.org/10.1128/jvi.02346-12.',
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