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Design, synthesis, molecular modeling, and anti-HIV-1 integrase activity of a series of photoactivatable diketo acid-containing inhibitors as affinity probes

Sechi, Mario and Carta, Fabrizio and Sannia, Luciano and Dallocchio, Roberto and Dessì, Alessandro and Al-Safi, Rasha I. and Neamati, Nouri (2009) Design, synthesis, molecular modeling, and anti-HIV-1 integrase activity of a series of photoactivatable diketo acid-containing inhibitors as affinity probes. Antiviral Research, Vol. 81 (3), p. 267-276. ISSN 0166-3542. Article.

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DOI: 10.1016/j.antiviral.2008.12.010

Abstract

The diketo acid (DKA) class of HIV-1 integrase (IN) inhibitors is thought to function by chelating divalent metal ions on the enzyme catalytic site. However, differences in mutations conferring resistance to various DKA inhibitors suggest that multiple binding orientations may exist. In order to facilitate identification of DKA binding sites, a series of photoactivable analogues of two potent DKAs was prepared as novel photoaffinity probes. In cross-linking assays designed to measure disruption of substrate DNA binding, the photoprobes behaved similarly to a reference DKA inhibitor. Molecular modeling studies suggest that such photoprobes interact within the IN active site in a manner similar to that of the parent DKAs. Analogues Ia-c are novel photoaffinity ligands useful in clarifying the HIV-1 binding interactions of DKA inhibitors.

Item Type:Article
ID Code:1910
Status:Published
Refereed:Yes
Uncontrolled Keywords:HIV-1 integrase inhibitors, diketo acids, photoaffinity labeling, photoprobes
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
002 Altri enti e centri di ricerca del Nord Sardegna > CNR-Consiglio Nazionale delle Ricerche > Istituto di chimica biomolecolare, Sassari
Publisher:Elsevier
ISSN:0166-3542
Additional Information:Pubblicato anche come contributo al congresso: SardiniaChem 2008: giornata di studio dedicata alla chimica organica delle molecole biologicamente attive, 30 Maggio 2008, Sassari, Italia.
Deposited On:18 Aug 2009 10:06

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