A Bifunctional SARS-CoV-2 Entry Inhibitor Targeting the Host Protease TMPRSS2 and Viral Spike Protein HR1 Region.

ABSTRACT: SARS-CoV-2 entry into host cells involves multiple steps and is a highly orchestrated process. Both the host protease TMPRSS2 and the HR1/HR2 segment within the spike (S) protein play a crucial role in promoting viral invasion. Herein, we report a series of bifunctional SARS-CoV-2 entry inhibitors formed by covalently linking a TMPRSS2 inhibitor, Camostat (Cm), and an HR1-targeting peptide fusion inhibitor IPB19 via a poly (ethylene glycol) (PEG) linker. Among them, IP4X and IP4Z display potent inhibitory activities against SARS-CoV-2 with similar IC₅₀ values of 0.16 μM and 0.17 μM, respectively. The efficacy surpassed that of their parent inhibitors by approximately 28-fold relative to Camostat and 15-fold relative to IPB19. We confirm that IP4X and IP4Z exhibit a dual-targetin

SUBMITTER: Wang H 

PROVIDER: S-EPMC12428505 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature