Toward the Discovery of Novel Anti-HIV Drugs. Second-Generation Inhibitors of the Cellular ATPase DDX3 with Improved Anti-HIV Activity: Synthesis, Structure-Activity Relationship Analysis, Cytotoxicity Studies, and Target Validation

Giovanni Maga, Federico Falchi, Marco Radi, Lorenzo Botta, Gianni Casaluce, Martina Bernardini, Hamid Irannejad, Fabrizio Manetti, Anna Garbelli, Alberta Samuele, Samantha Zanoli, José A. Esté, Emmanuel Gonzalez, Elisa Zucca, Stefania Paolucci, Fausto Baldanti, Jan DeRijck, Zeger Debyser, Maurizio Botta

Research output: Contribution to journalArticle

Abstract

A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.

Original languageEnglish
Pages (from-to)1371-1389
Number of pages19
JournalChemMedChem
Volume6
Issue number8
DOIs
Publication statusPublished - Aug 1 2011

Keywords

  • Antiviral agents
  • DDX3
  • Helicase
  • HIV-1
  • Host cofactors
  • Inhibitors

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

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    Maga, G., Falchi, F., Radi, M., Botta, L., Casaluce, G., Bernardini, M., Irannejad, H., Manetti, F., Garbelli, A., Samuele, A., Zanoli, S., Esté, J. A., Gonzalez, E., Zucca, E., Paolucci, S., Baldanti, F., DeRijck, J., Debyser, Z., & Botta, M. (2011). Toward the Discovery of Novel Anti-HIV Drugs. Second-Generation Inhibitors of the Cellular ATPase DDX3 with Improved Anti-HIV Activity: Synthesis, Structure-Activity Relationship Analysis, Cytotoxicity Studies, and Target Validation. ChemMedChem, 6(8), 1371-1389. https://doi.org/10.1002/cmdc.201100166