Evidence map›Paper›PMID 36052369›Full record

ArticleResearch square2022

A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations.

Jin Ou, Eric M Lewandowski, Yanmei Hu, Austin A Lipinski, Ryan T Morgan, Lian M C Jacobs, Xiujun Zhang, Melissa J Bikowitz, Paul Langlais, Haozhou Tan and 3 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in Research square, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 7 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 4 institutions in 2 countries.

Jin OuDepartment of Biology, School of Arts and Sciences, The Catholic University of America, Washington, DC 20064, United States.
Eric M LewandowskiDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States.
Yanmei HuDepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, 08854, United States.
Austin A LipinskiDepartment of Medicine, College of Medicine, University of Arizona, Tucson, AZ 85724, United States.
Ryan T MorganDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States.
Lian M C JacobsDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States.
Xiujun ZhangDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States.
Melissa J BikowitzDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States.
Paul LanglaisDepartment of Medicine, College of Medicine, University of Arizona, Tucson, AZ 85724, United States.
Haozhou TanDepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, 08854, United States.
Jun WangDepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, 08854, United States.ORCID 0000-0002-4845-4621
Yu ChenDepartment of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States.ORCID 0000-0002-5115-3600
John S ChoyDepartment of Biology, School of Arts and Sciences, The Catholic University of America, Washington, DC 20064, United States.
University of South Florida · USRutgers, The State University of New Jersey · USCatholic University of America · USUniversity of Arizona · US

Funding

Development of dual inhibitors targeting the viral main protease and the host cathepsin L as SARS-CoV-2 antiviralsR01AI158775 · NIAID · UNIVERSITY OF ARIZONA · PI Jun Wang · 2021 to 2026
$3.6M
Heterogeneous synthetic microbiome constructed with biopolymer fluitrodesR15GM129766 · NIGMS · CATHOLIC UNIVERSITY OF AMERICA · PI CHOY, JOHN SING, LUO, XIAOLONG · 2018 to 2018
$465k
NIAID NIH HHS R01 AI158775NIGMS NIH HHS R15 GM129766
6 · The paper itself

Abstract

The SARS-CoV-2 main protease (Mpro) is a major therapeutic target. The Mpro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As Mpro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as a proxy for Mpro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays showed that an E166R substitution conferred strong nirmatrelvir resistance while an E166N mutation compromised activity. On the other hand, N142A and P132H mutations caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of Mpro E166R, and Mpro E166N, providing insights into how arginine may drive drug resistance while asparagine leads to reduced activity. The work presented here will help characterize novel resistant variants of Mpro that may arise as Mpro antivirals become more widely used.

Identifiers

PMID36052369
PMCPMC9435405
OpenAlexW4293149823

What Socratic holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.