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Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: riccardo zenezini chiozzi

LAB HEAD: Konstantinos Thalassinos

PROVIDER: PXD057024 | Pride | 2024-11-29

REPOSITORIES: Pride

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			Action	DRS
	03082023_RZC_STP0052_DIA_Condition1_Drug10_01.htrms	Other
	03082023_RZC_STP0052_DIA_Condition1_Drug10_01.raw	Raw
	03082023_RZC_STP0052_DIA_Condition1_Drug10_02.htrms	Other
	03082023_RZC_STP0052_DIA_Condition1_Drug10_02.raw	Raw
	03082023_RZC_STP0052_DIA_Condition1_Drug10_03.htrms	Other

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