2023
DOI: 10.21203/rs.3.rs-2639894/v1
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Synthetic PROTACs based on a depsipeptide macrocycle selectively degrade cyclophilin A and inhibit HIV-1

Abstract: We have designed and characterised PROteolysis TArgeting Chimeras (PROTACs) active against the human protein cyclophilin A (CypA), a viral cofactor required for efficient replication of a series of unrelated viruses. Our cyclophilin PROTACs have fully synthetic macrocycle warheads derived from Sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporin A, and do not have immunosuppressive activity. They effectively degrade CypA, with selectivity over CypB, in a ubiquitin depe… Show more

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Cited by 2 publications
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“…4, A to D , gray lines). Both CsA and TWH106 [a CypA inhibitor structurally distinct to CsA ( 27 )] rescued infectivity of restricting cells through CypA inhibition ( Fig. 4, A and B , open circles).…”
Section: Resultsmentioning
confidence: 99%
“…4, A to D , gray lines). Both CsA and TWH106 [a CypA inhibitor structurally distinct to CsA ( 27 )] rescued infectivity of restricting cells through CypA inhibition ( Fig. 4, A and B , open circles).…”
Section: Resultsmentioning
confidence: 99%
“…As PROTACs can function sub-stoichiometrically, they can be used at low concentrations [ 30 ]. Therefore, developing PROTAC compounds represents an avenue particularly attractive for inhibiting targets with high cellular concentrations such as CypA [ 31 , 32 , 33 ]. Moreover, PROTAC represents an “event-driven” pharmacological mechanism rather than an occupation-driven effect [ 34 ].…”
Section: Introductionmentioning
confidence: 99%