Development of a Novel Fusion Inhibitor against T-20-resistant HIV-1
T-20 (also known as Fuzeon and enfuvirtide) is a potent human immunodeficiency virus-1 (HIV-1) fusion inhibitory peptide derived from a C-terminal heptad repeat (C-HR) of envelope glycoprotein gp41 . Although even multi-drug-resistant HIV variants are effectively suppressed by T-20-containing regimens in the treatment of HIV/AIDS, it has been reported that T-20-resistant HIV strains can emerge after prolonged therapy .
Another C-HR-derived peptide C34 also exhibits potent anti-HIV activity by inhibiting the fusogenic six-helical bundle formation. It has been revealed that binding of C34 with the coiled-coil structure of an N-terminal heptad repeat (N-HR) occurs in α helix conformations, while the binding mode of T-20 remains ambiguous . Previously, we have demonstrated that replacement of the i, i + 4 residues at solvent-accessible sites of C34 with Glu or Lys leads to stabilization of the six-helical bundle by potential salt-bridge formation of Glu—Lys pairs ....
KeywordsHelix Structure Fusion Inhibitor Envelope Glycoprotein Gp41 Original Amino Acid Cosmosil 5C18
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Health and Labour Sciences Research Grants (Research on HIV/AIDS). H.N. is grateful for Research Fellowships from the JSPS for Young Scientists.