PXD057024-1

PXD057024 is an original dataset announced via ProteomeXchange.

Title	Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV
Description	We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporin A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells, and this degradation is via a PROTAC mechanism. These molecules have high specificity for CypA illustrated by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA targeting PROTACs inhibit viral replication potently, and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.
HostingRepository	PRIDE
AnnounceDate	2024-11-29
AnnouncementXML	Submission_2024-11-29_04:54:10.399.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	riccardo zenezini chiozzi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-21 11:45:34	ID requested
⏵ 1	2024-11-29 04:54:10	announced

Dataset with its publication pending

submitter keyword: proteomics, DIA,HIV, PROTAC

Konstantinos Thalassinos
contact affiliation	University College London, Institute of Structural and Molecular Biology, Darwin Building Room 101A, London, WC1E 6BT, United Kingdom
contact email	k.thalassinos@ucl.ac.uk
lab head
riccardo zenezini chiozzi
contact affiliation	UCL
contact email	r.chiozzi@ucl.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057024
     1. Label: PRIDE project
     2. Name: Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV