A possible improvement for structure-based drug design illustrated by the discovery of a Tat HIV-1 inhibitor

• Published in: Bioorganic & medicinal chemistry letters 2004-03, Vol.14 (6), p.1543-1546
• Main Authors: Montembault, Mickaël, Vo-Thanh, Giang, Deyine, Abdallah, Fargeas, Valérie, Villiéras, Monique, Adjou, Ané, Dubreuil, Didier, Esquieu, Didier, Grégoire, Catherine, Opi, Sandrine, Péloponèse, Jean-Marie, Campbell, Grant, Watkins, Jennifer, de Mareuil, Jean, Aubertin, Anne-Marie, Bailly, Christian, Loret, Erwann, Lebreton, Jacques
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Chemical Sciences; Drug Design; Gene Products, tat - antagonists & inhibitors; Gene Products, tat - metabolism; HIV; HIV-1 - drug effects; HIV-1 - metabolism; Humans; Inhibitor; Medical sciences; Organic chemistry; Pharmacology. Drug treatments; Structure-Activity Relationship; tat Gene Products, Human Immunodeficiency Virus; Tat protein
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.12.095

The HIV-1 Tat protein is a promising target for AIDS therapy, due to its extra-cellular roles against the immune system. From the 2D-NMR structure of Tat, we have designed molecules, called TDS, able to bind to Tat and inhibit HIV-1 replication in vitro. This new family of antivirals is composed of a triphenylene aromatic ring substituted with at least one carbon chain bearing a succinimide group. These ligands are prepared from triphenylene or 2,6,10-trimethylphenylene in 3–6 steps depending on the target molecule. A new family of antivirals able to bind on protein Tat and inhibit in vitro HIV-1 replication has been synthesized.