Evidence map›Paper›PMID 35364007›Full record

ArticleCell chemical biology2022

Inhibiting a dynamic viral protease by targeting a non-catalytic cysteine.

Kaitlin R Hulce, Priyadarshini Jaishankar, Gregory M Lee, Markus-Frederik Bohn, Emily J Connelly, Kristin Wucherer, Chayanid Ongpipattanakul, Regan F Volk, Shih-Wei Chuo, Michelle R Arkin and 2 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
1.7field-weighted citation impact, top 16% of its field
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

6 citing papers in PubMed, 12 citations in OpenAlex.

  1. Article
  2. Antibody Reveals Conformational Latch Controlling Herpesvirus Proteases.bioRxiv : the preprint server for biology · 2025
    Article
  3. Article
  4. Review
  5. Article
  6. Article
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

12 authors at 1 institution in 1 country.

Kaitlin R HulceDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Priyadarshini JaishankarDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA; Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Gregory M LeeDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA; Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Markus-Frederik BohnDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Emily J ConnellyDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Kristin WuchererDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Chayanid OngpipattanakulDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Regan F VolkDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Shih-Wei ChuoDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Michelle R ArkinDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA; Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Adam R RensloDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA; Small Molecule Discovery Center, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA.
Charles S CraikDepartment of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, Genentech Hall, San Francisco, CA 94143-2280, USA. Electronic address: charles.craik@ucsf.edu.
University of California, San Francisco · US

Funding

X-ray Screening and Rapid Structure DeterminationP50GM082250 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KROGAN, NEVAN J · 2007 to 2018
$48.8M
User Training and OutreachP30GM124169 · NIGMS · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI PAUL David ADAMS, Gregory L Hura · 2017 to 2026
$28.6M
X-ray Screening and Rapid Structure DeterminationP50AI150476 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KROGAN, NEVAN J · 2019 to 2021
$14.4M
Structure Biology and Targeted Drug Design for AIDSP01GM056531 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI ORTIZ DE MONTELLANO, PAUL R · 1997 to 2006
$11.0M
RESEARCH TRAINING IN CHEMISTRY AND CHEMICAL BIOLOGYT32GM064337 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CRAIK, CHARLES SCOTT · 2002 to 2021
$7.8M
PHARMACEUTICAL SCIENCES AND PHARMACOGENOMICST32GM007175 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI AHITUV, NADAV, KROETZ, DEANNA L · 1985 to 2021
$7.1M
Research Training in Chemistry and Chemical BiologyT32GM145460 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Jason E Gestwicki · 2022 to 2026
$3.1M
Eliminating Critical Systematic Errors In Structural Biology With Next-Generation SimulationR01GM124149 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI HOLTON, JAMES M · 2017 to 2024
$2.5M
Allosteric Inhibition of a Family of Proteolytic EnzymesR01GM104659 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CRAIK, CHARLES SCOTT · 2013 to 2016
$1.2M
Targeting Allosteric Studies to Modulate Protein Interactions and FunctionR01AI067423 · NIAID · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CRAIK, CHARLES SCOTT · 2007 to 2009
$1.1M
NIAID NIH HHS P50 AI150476NIAID NIH HHS R01 AI067423NIGMS NIH HHS P01 GM056531NIGMS NIH HHS P30 GM124169NIGMS NIH HHS P50 GM082250NIGMS NIH HHS R01 GM104659NIGMS NIH HHS R01 GM124149NIGMS NIH HHS T32 GM007175NIGMS NIH HHS T32 GM064337NIGMS NIH HHS T32 GM145460
6 · The paper itself

Abstract

Viruses are responsible for some of the most deadly human diseases, yet available vaccines and antivirals address only a fraction of the potential viral human pathogens. Here, we provide a methodology for managing human herpesvirus (HHV) infection by covalently inactivating the HHV maturational protease via a conserved, non-catalytic cysteine (C161). Using human cytomegalovirus protease (HCMV Pr) as a model, we screened a library of disulfides to identify molecules that tether to C161 and inhibit proteolysis, then elaborated hits into irreversible HCMV Pr inhibitors that exhibit broad-spectrum inhibition of other HHV Pr homologs. We further developed an optimized tool compound targeted toward HCMV Pr and used an integrative structural biology and biochemical approach to demonstrate inhibitor stabilization of HCMV Pr homodimerization, exploiting a conformational equilibrium to block proteolysis. Irreversible HCMV Pr inhibition disrupts HCMV infectivity in cells, providing proof of principle for targeting proteolysis via a non-catalytic cysteine to manage viral infection.

Indexed as

CytomegalovirusCytomegalovirus InfectionsCysteineHumansPeptide HydrolasesViral ProteasesCysteinePeptide HydrolasesViral Proteasesallosteryantiviralconformational dynamicscovalent inhibitorcytomegalovirusdimerizationherpesvirusirreversible electrophilenon-catalytic cysteineprotease

Identifiers

PMID35364007
PMCPMC9133232
OpenAlexW4221095631

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.