Discovery of Small-Molecule Inhibitors of the ATPase Activity of Human Papillomavirus E1 Helicase

• Published in: Journal of medicinal chemistry Vol. 47; no. 1; pp. 18 - 21
• Main Authors: Faucher, Anne-Marie, White, Peter W, Brochu, Christian, Grand-Maître, Chantal, Rancourt, Jean, Fazal, Gulrez
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.01.2004; Amer Chemical Soc
• Subjects: Acetates - chemical synthesis; Acetates - chemistry; Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Biological and medical sciences; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Chemistry, Medicinal; Humans; Life Sciences & Biomedicine; Medical sciences; Oncogene Proteins, Viral - antagonists & inhibitors; Oncogene Proteins, Viral - chemistry; Papillomaviridae - enzymology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Structure-Activity Relationship; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfone; Enzyme; Adenosinetriphosphatase; Benzene derivatives; Enzyme inhibitor; Papovaviridae; In vitro; Naphthalene derivatives; Papillomavirus; Virus; Human papillomavirus; Structure activity relation; Carboxylic acid; Hydrolases; Antiviral
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm034206x

The Boehringer Ingelheim compound collection was screened for inhibitors of the ATPase activity of human papillomavirus E1 helicase to develop antiviral agents that inhibit human papillomavirus (HPV) DNA replication. This screen led to the discovery of (biphenyl-4-sulfonyl)acetic acid 1, which inhibits the ATPase activity of HPV type 6 E1 helicase with a low micromolar IC50 value. A hit-to-lead exercise rapidly converted 1 into a low nanomolar lead series.