RESUMEN
Different from most antiretroviral drugs that act as passive defenders to inhibit HIV-1 replication inside the host cell, virus inactivators can attack and inactivate HIV-1 virions without relying on their replication cycle. Herein, we describe the discovery of a hydrocarbon double-stapled helix peptide, termed D26. D26 is based on the HIV-1 gp41 protein lentiviral lytic peptide-3 motif (LLP3) sequence, which can efficiently inhibit HIV-1 infection and inactivate cell-free HIV-1 virions. It was noted that D26 was highly resistant to proteolytic degradation and exhibited a remarkably extended in vivo elimination half-life. Additionally, relative to its linear, nonstapled version, D26 exhibited much higher exposure in sanctuary sites for HIV-1. Amazingly, this lead compound also demonstrated detectable oral absorption. Thus, it can be concluded that D26 is a promising candidate for further development as a long-acting, orally applicable HIV-1 inactivator for the treatment of HIV-1 infection.
Asunto(s)
Fármacos Anti-VIH , Disponibilidad Biológica , Proteína gp41 de Envoltorio del VIH , VIH-1 , Péptidos , VIH-1/efectos de los fármacos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Humanos , Animales , Administración Oral , Proteína gp41 de Envoltorio del VIH/metabolismo , Proteína gp41 de Envoltorio del VIH/química , Péptidos/química , Péptidos/farmacología , Péptidos/farmacocinética , Descubrimiento de Drogas , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , SemividaRESUMEN
Interaction between Middle East respiratory syndrome coronavirus (MERS-CoV) spike (S) protein heptad repeat-1 domain (HR1) and heptad repeat-2 domain (HR2) is critical for the MERS-CoV fusion process. This interaction is mediated by the α-helical region from HR2 and the hydrophobic groove in a central HR1 trimeric coiled coil. We sought to develop a short peptidomimetic to act as a MERS-CoV fusion inhibitor by reproducing the key recognition features of HR2 helix. This was achieved by the use of helix-stabilizing strategies, including substitution with unnatural helix-favoring amino acids, introduction of ion pair interactions, and conjugation of palmitic acid. The resulting 23-mer lipopeptide, termed AEEA-C16, inhibits MERS-CoV S protein-mediated cell-cell fusion at a low micromolar level comparable to that of the 36-mer HR2 peptide HR2P-M2. Collectively, our studies provide new insights into developing short peptide-based antiviral agents to treat MERS-CoV infection.