Prospects and strategies for the discovery and development of small-molecule inhibitors of six-helix bundle formation in class 1 viral fusion proteins.
Class I viral fusion proteins have an important role in the fusion of viral membranes with host cell membranes, a critical step in the viral life-cycle. These proteins all have similar structural features and form six-helix bundles in their fusogenic form, a general mechanism of action for virus-cell fusion. The successful discovery of peptide-based inhibitors of fusion proteins, in addition to the US Food and Drug Administration approval of one of these inhibitors as an anti-HIV-1 drug, confirmed that the inhibition of six-helix bundle formation is a viable strategy for identifying antiviral drugs. Because peptide-based drugs have several limitations, research has been undertaken to identify potent small-molecule inhibitors of six-helix bundle formation in a variety of viruses, including HIV-1, human respiratory syncytial virus and measles virus. Small-molecule inhibitors that disrupt six-helix bundle formation and prevent viral infection have been identified. This review will focus on the discovery of these small-molecule inhibitors.
Debnath
Asim K
AK
Lindsley F Kimball Research Institute of the New York Blood Center, Laboratory of Molecular Modeling & Drug Design, New York, NY 10021, USA. adebnath@nybloodcenter.org
D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D044482:Benzeneacetamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008459:Measles virus / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D017433:Protein Structure, Secondary; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000627:Aminophenols; D000998:Antiviral Agents; C482453:BMS 433771; D044482:Benzeneacetamides; D001562:Benzimidazoles; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; C505393:N-(5-amino-2-hydroxyphenyl)-2-phenylacetamide; D010446:Peptide Fragments; D014760:Viral Fusion Proteins; D000077560:Enfuvirtide