Evidence map›Paper›PMID 38659941›Full record

ArticlebioRxiv : the preprint server for biology2024

PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2.

Marwah Karim, Manjari Mishra, Chieh-Wen Lo, Sirle Saul, Halise Busra Cagirici, Do Hoang Nhu Tran, Aditi Agrawal, Luca Ghita, Amrita Ojha, Michael P East and 17 more

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

Article in bioRxiv : the preprint server for biology, 2024. 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, 2 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors at 9 institutions in 5 countries.

Marwah KarimDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Manjari MishraDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Chieh-Wen LoDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Sirle SaulDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Halise Busra CagiriciDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Do Hoang Nhu TranDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Aditi AgrawalDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Luca GhitaDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Amrita OjhaDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Michael P EastDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Karen Anbro GammeltoftDepartment of Infectious Diseases, University of Copenhagen, Denmark. Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen.
Malaya Kumar SahooDepartment of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Gary L JohnsonDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Soumita DasBiomedical & Nutritional Science, Center for Pathogen Research & Training (CPRT), University of Massachusetts-Lowell, USA.
Dirk JochmansKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
Courtney A CohenUS Army Medical Research Institute of Infectious Diseases, Viral Immunology Branch, Frederick, Maryland, USA.
Judith GottweinDepartment of Infectious Diseases, University of Copenhagen, Denmark. Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen.
John DyeUS Army Medical Research Institute of Infectious Diseases, Viral Immunology Branch, Frederick, Maryland, USA.
Norma NeffChan Zuckerberg Biohub, San Francisco, CA, 94158, USA.
Benjamin A PinskyDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Tuomo LaitinenSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Finland.
Tatu PantsarSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Finland.
Antti PosoSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Finland.
Fabio ZaniniSchool of Clinical Medicine, UNSW Sydney, Sydney, New South Wales, Australia.
Steven De JongheKU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.
Christopher R M AsquithSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Finland.
Shirit EinavDepartment of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA.
Stanford University · USUniversity of Eastern Finland · FIChan Zuckerberg Initiative (United States) · USRega Institute for Medical Research · BEUnited States Army Medical Research Institute of Infectious Diseases · USUniversity of Copenhagen · DKUniversity of North Carolina at Chapel Hill · USUniversity of Massachusetts Lowell · USUNSW Sydney · AU

Funding

Illuminating Function of the Understudied Druggable KinomeU24DK116204 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI JOHNSON, GARY L. · 2017 to 2022
$13.6M
EMERGING INFECTIOUS DISEASEST32AI007502 · NIAID · STANFORD UNIVERSITY · PI Prasanna Jagannathan, DAVID A. RELMAN · 1995 to 2026
$6.8M
Advancing the development of a novel class of small molecules for treating pan-coronavirus infectionsR01AI158569 · NIAID · STANFORD UNIVERSITY · PI EINAV, SHIRIT · 2021 to 2025
$3.7M
Innate responses following infection with enteric microbesR01DK107585 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DAS, SOUMITA · 2016 to 2020
$2.2M
NIAID NIH HHS R01 AI158569NIAID NIH HHS T32 AI007502NIDDK NIH HHS R01 DK107585NIDDK NIH HHS U24 DK116204
6 · The paper itself

Abstract

In search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We discovered PIP4K2C's roles in SARS-CoV-2 entry, RNA replication, and assembly/egress, validating it as a druggable antiviral target. Integrating proteomics, single-cell transcriptomics, and functional assays revealed that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced impairment of autophagic flux. Reversing this autophagic flux impairment is a mechanism of antiviral action of RMC-113. These findings reveal virus-induced autophagy regulation via PIP4K2C, an understudied kinase, and propose dual inhibition of PIP4K2C and PIKfyve as a candidate strategy to combat emerging viruses.

Identifiers

PMID38659941
PMCPMC11042293
OpenAlexW4394929322

What OpenQuestion 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 OpenQuestion graph.