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Investigating the role of metal chelation in HIV-1 integrase strand transfer inhibitors

Bacchi, Alessia and Carcelli, Mauro and Compari, Carlotta and Fisicaro, Emilia and Pala, Nicolino and Rispoli, Gabriele and Rogolino, Dominga and Sanchez, Tino W. and Sechi, Mario and Sinisi, Valentina and Neamati, Nouri (2011) Investigating the role of metal chelation in HIV-1 integrase strand transfer inhibitors. Journal of Medicinal Chemistry, Vol. 54 (24), p. 8407-8420. eISSN 1520-4804. Article.

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DOI: 10.1021/jm200851g


HIV-1 integrase (IN) has been validated as an attractive target for the treatment of HIV/AIDS. Several studies have confirmed that the metal binding function is a crucial feature in many of the reported IN inhibitors. To provide new insights on the metal chelating mechanism of IN inhibitors, we prepared a series of metal complexes of two ligands (HL1 and HL2), designed as representative models of the clinically used compounds raltegravir and elvitegravir. Potentiometric measurements were conducted for HL2 in the presence of Mg(II), Mn(II), Co(II), and Zn(II) in order to delineate a metal speciation model. We also determined the X-ray structures of both of the ligands and of three representative metal complexes. Our results support the hypothesis that several selective strand transfer inhibitors preferentially chelate one cation in solution and that the metal complexes can interact with the active site of the enzyme.

Item Type:Article
ID Code:6862
Uncontrolled Keywords:HIV-1 integrase (IN), ligands HL1 and HL2
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze del farmaco
Publisher:American Chemical Society
Deposited On:19 Dec 2011 08:49

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