Publication date: Aug 26, 2025
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 IC 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-targeting mechanism by binding to both TMPRSS2 and HR1 region of S protein. These findings highlight the potential of the bifunctional inhibitors for further development as a novel multitarget therapy against SARS-CoV-2 infection and enrich the understanding of S-mediated entry of SARS-CoV-2 into host cells.
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| Concepts | Keywords |
|---|---|
| Ip4x | 6-HB |
| Potent | entry inhibitors |
| Protease | multi-target-directed ligands |
| Therapy | SARS-CoV-2 |
| Viral | TMPRSS2 |