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

doi:10.1002/cmdc.201100166

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

IRCCS Fondazione Policlinico San Matteo

Research output: Contribution to journal › Article

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 language	English
Pages (from-to)	1371-1389
Number of pages	19
Journal	ChemMedChem
Volume	6
Issue number	8
DOIs	https://doi.org/10.1002/cmdc.201100166
Publication status	Published - 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

Access to Document

10.1002/cmdc.201100166

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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

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

In: ChemMedChem, Vol. 6, No. 8, 01.08.2011, p. 1371-1389.

Research output: Contribution to journal › Article

Maga, G, Falchi, F, Radi, M, Botta, L, Casaluce, G, Bernardini, M, Irannejad, H, Manetti, F, Garbelli, A, Samuele, A, Zanoli, S, Esté, JA, 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, vol. 6, no. 8, pp. 1371-1389. https://doi.org/10.1002/cmdc.201100166

Maga G, Falchi F, Radi M, Botta L, Casaluce G, Bernardini M et al. 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. 2011 Aug 1;6(8):1371-1389. https://doi.org/10.1002/cmdc.201100166

Maga, Giovanni ; Falchi, Federico ; Radi, Marco ; Botta, Lorenzo ; Casaluce, Gianni ; Bernardini, Martina ; Irannejad, Hamid ; Manetti, Fabrizio ; Garbelli, Anna ; Samuele, Alberta ; Zanoli, Samantha ; Esté, José A. ; Gonzalez, Emmanuel ; Zucca, Elisa ; Paolucci, Stefania ; Baldanti, Fausto ; DeRijck, Jan ; Debyser, Zeger ; Botta, Maurizio. / 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. In: ChemMedChem. 2011 ; Vol. 6, No. 8. pp. 1371-1389.

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