Design of a modular tetrameric scaffold for the synthesis of membrane-localized D-peptide inhibitors of HIV-1 entry

The highly conserved HIV-1 gp41 "pocket" region is a promising target for inhibiting viral entry. PIE12-trimer is a protease-resistant trimeric d-peptide inhibitor that binds to this pocket and potently blocks HIV entry. PIE12-trimer also possesses a reserve of binding energy that provides it with a strong genetic barrier to resistance ("resistance capacitor"). Here, we report the design of a modular scaffold employing PEGs of discrete lengths for the efficient optimization and synthesis of PIE12-trimer. This scaffold also allows us to conjugate PIE12-trimer to several membrane-localizing cargoes, resulting in dramatically improved potency and retention of PIE12-trimer's ability to absorb the impact of resistance mutations. This scaffold design strategy should be of broad utility for the rapid prototyping of multimeric peptide inhibitors attached to potency- or pharmacokinetics-enhancing groups.