Peptide, peptidomimetic and small-molecule drug discovery targeting HIV-1 host-cell attachment and entry through gp120, gp41, CCR5 and CXCR4.

This review highlights selected examples of peptide, peptidomimetic and small-molecule drug discovery targeting HIV-1 to advance novel anti-HIV pharmaceuticals that inhibit initial stages of the viral cycle; namely, attachment and entry. Some of these approaches have culminated in the development of peptide-based drugs, while other have exploited peptides as enabling tools toward the identification of small-molecule lead compounds. Both of these conceptually different approaches have facilitated lead optimization of molecules with complementary and often surprising anti-HIV pharmacological properties, supporting their role in pharmaceutical development. Furthermore, such molecules enabled mechanistic elucidation of viral attachment and entry and provided additional insights toward achieving the desired drug profile.