Permanent Inhibition of Viral Entry by Covalent Entrapment of HIV gp41 on the Virus Surface

HIV entry occurs by concerted conformational changes in the envelope protein complex on the surface of the virus. This complex is made up of a trimer of heterodimers of two subunits: surface subunit, gp120, and transmembrane subunit, gp41. Conformational changes in the envelope complex allow gp41 to mediate membrane fusion leading to exposure of two gp41 regions: N-heptad repeat (NHR) and C-heptad repeat (CHR). Peptides from the NHR or the CHR have been found to inhibit HIV entry. Herein we show that we can covalently inhibit HIV viral entry by permanently trapping the gp41 intermediate on the virus surface using a covalently reactive group on inhibitory peptides. This is evidence showing that vulnerable conformational intermediates exist transiently during HIV viral entry, and the details presented herein will facilitate development of envelope as a target for therapeutics and potential chemopreventive agents that could disable the virus before contact with the host cell.