Evidence map›Paper›PMID 40183562›Full record

ArticlemBio2025

Molecular mechanisms of drug resistance and compensation in SARS-CoV-2 main protease: the interplay between E166 and L50.

Sarah N Zvornicanin, Ala M Shaqra, Julia Flynn, Heidi Carias Martinez, Weiping Jia, Stephanie Moquin, Dustin Dovala, Daniel N Bolon, Nese Kurt Yilmaz, Celia A Schiffer

Abstract read
In one paragraph

Article in mBio, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

4 citing papers in PubMed.

  1. Trial
  2. Article
  3. Article
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Sarah N ZvornicaninDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.ORCID 0000-0003-0282-1809
Ala M ShaqraDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.ORCID 0000-0001-6994-2416
Julia FlynnDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.ORCID 0000-0002-5490-393X
Heidi Carias MartinezBiomedical Research, Novartis, Emeryville, California, USA.
Weiping JiaBiomedical Research, Novartis, Emeryville, California, USA.
Stephanie MoquinBiomedical Research, Novartis, Emeryville, California, USA.
Dustin DovalaBiomedical Research, Novartis, Emeryville, California, USA.
Daniel N BolonDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.ORCID 0000-0001-5857-6676
Nese Kurt YilmazDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.ORCID 0000-0002-5036-676X
Celia A SchifferDepartment of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA.ORCID 0000-0003-2270-6613

Funding

Defining and Avoiding Molecular Mechanisms of Drug ResistanceR35GM151996 · NIGMS · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI Celia A. Schiffer · 2024 to 2026
$1.5M
Structure-based Antiviral Design against HTLV-1 ProteaseF31AI179014 · NIAID · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI ZVORNICANIN, SARAH N · 2023 to 2025
$77k
HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) F31AI179014HHS | NIH | National Institute of General Medical Sciences (NIGMS) R35GM151996NIAID NIH HHS F31 AI179014NIGMS NIH HHS R35 GM151996Novartis AG | Novartis Institutes for BioMedical Research (NIBR)
6 · The paper itself

Abstract

The SARS-CoV-2 main protease (M IMPORTANCE: Drug resistance remains a great challenge to modern medicine. This study investigates SARS-CoV-2 main protease variants E166A and E166V which confer nirmatrelvir resistance. These variants can retain considerable enzymatic activity through combination with the compensatory mutation L50F. For single- and double-mutant variant enzymes, we assessed catalytic efficiency, measured loss in potency for nirmatrelvir and its analog PF-00835231, and cocrystallized with inhibitors to investigate drug resistance caused by these mutations. Our results contribute toward understanding of molecular mechanisms of resistance and combinations of mutations, which pushes toward resistance-thwarting inhibitor design. These principles also apply broadly to many quickly evolving drug targets in infectious diseases.

Indexed as

Antiviral AgentsCoronavirus 3C ProteasesDrug Resistance, ViralSARS-CoV-2Catalytic DomainCOVID-19COVID-19 Drug TreatmentHumansIndolesLactamsLeucineMutationNitrilesProline3C-like proteinase, SARS-CoV-2Antiviral AgentsCoronavirus 3C ProteasesIndolesLactamsLeucinenirmatrelvirNitrilesProlineantiviral agentscrystal structuredrug resistance mechanismsprotease inhibitorsprotein structure-functionproteolytic enzymesresistance mutations

Identifiers

PMID40183562
PMCPMC12077200

What OpenQuestion holds

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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 OpenQuestion graph.