Abstract

Hydrocarbon stapling can restore bioactive α-helical structure to natural peptides, yielding research tools and prototype therapeutics to dissect and target protein interactions. The capacity of peptide stapling to generate high-fidelity, protease-resistant mimics of antigenic structures for vaccine development has been previoulsy explored. HIV-1 has been refractory to vaccine technologies thus far, although select human antibodies can broadly neutralize HIV-1 by targeting sequences of the gp41 juxtamembrane fusion apparatus. Candidate HIV-1 immunogens, have been generated and characterized stabilized α-helices of the membrane-proximal external region (SAH-MPER) of gp41 have been utilized. SAH-MPER peptides were remarkably protease resistant and bound to the broadly neutralizing 4E10 and 10E8 antibodies with high affinity, recapitulating the structure of the MPER epitope when differentially engaged by the two anti-HIV Fabs. Here, we discovered for the first time the GENEA-StacHIVenar-10085 utilising a computer aided generation of a prototype superset Stapled HIV-1 peptide-similar full-match pharmacophoric poly-agent recapitulating antigenic viral replication structures bounded broadly targeted to the neutralizing 4E10 and 10E8 antibodies.

Keywords

computer-aided; predicted;Stapled-HIV-1;peptide-mimic;pharmacophoric-poly-agent;
recapitulating-antigenic;structures;computer aided; generation; prototype; superset; Stapled HIV-1; peptide-similar; full-match; pharmacophoric; poly-agent; recapitulating antigenic; viral replication; structures; bounded broadly; neutralizing 4E10 and 10E8 antibodies;