Peptide Bispecifics Inhibiting HIV-1 Infection by an Orthogonal Chemical and Supramolecular Strategy

Viral infections pose a significant threat to human health and effective antiviral strategies are urgently needed. Antiviral peptides have emerged as a promising class of therapeutic agents due to their unique properties and mechanisms of action. While effective on their own, combining antiviral peptides may allow to enhance antiviral activity, broaden the antiviral spectrum, and prevent viral resistance. Here, we developed an orthogonal chemical strategy to prepare a heterodimeric peptide conjugate assembled on a protein-based nanoplatform. Specifically, we combined optimized version of two peptides inhibiting HIV-1 by distinct mechanisms. Virus-inhibitory peptide (VIRIP) is a 20 amino acid fragment of α1-antitrypsin that inhibits HIV-1 by targeting the gp41 fusion peptide. Endogenous Peptide Inhibitor of CXCR4 (EPI-X4) is a 16-residue fragment of human serum albumin that prevents HIV-1 entry by binding to the viral CXCR4 coreceptor. We assembled supramolecular nanoplatforms carrying biotinylated optimized forms of both peptides. We show that the tetravalent, bispecific assemblies show increased activity against CXCR4-tropic HIV-1variants. Our results are proof-of-concept that antiviral peptides with different modes of action can be assembled on nanoplatforms without loss of activity.