HIV integrase is a vital enzyme in the life cycle of the human immunodeficiency virus (HIV-1), as it is responsible for the integration of viral DNA into the host genome.  This 288-residue protein has no identical human cellular homologue making it an attractive target for the design of HIV-1 therapeutics.  This fact as well as the essential nature of HIV-1 integrase in viral replication has made it the focus of numerous inhibition efforts.  Peptides derived from the interfacial region of dimeric HIV-1 integrase have been evaluated as inhibitors of integrase's 3'-endonuclease activity and three peptides were found to be moderately potent inhibitors.  While each interfacial peptide is known to assume a distinct α-helical secondary structure in the context of the integrase protein, the peptides adopted a random coil conformation in aqueous media.  Therefore, an investigation was undertaken to determine the role of secondary structure on the dimerization inhibition of integrase.  To this end, a hydrocarbon staple was employed to constrain the random coil α5 peptide into an α-helical conformation.  This staple was formed by the synthesis and incorporation of two unnatural amino acids containing alkene side chains into the peptide sequence.  The amino acid side chains were then coupled via olefin metathesis to afford a hydrocarbon staple.  Peptide design, monomer synthesis, and peptide synthesis of the constrained peptides and control peptides were undertaken and resulted in increased helical character and enhanced 3'-processing inhibitory potency for all constrained moieties. 

Figure 1. Unnatural amino acids containing alkene side chains incorporated into an HIV-1 integrase interfacial peptide inhibitor shown in a constrained α-helical conformation; Metathesized side chain shown in green