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Novel anti-RT drugs for HIV-1 infection treatment


In our laboratory we are currently screening novel anti-RT compounds in an effort aimed to identify new potential lead compounds for the development of more potent and broad-spectrum anti-HIV drugs.


The reverse transcriptase (RT) inhibitors, both nucleoside- (NRTIs) and non-nucleoside-analogs (NNRTIs), still represent the majority of the clinically used anti-HIV drugs and constitute the main backbone of currently employed combinatorial regimens. A major obstacle to successfull chemotherapic eradication of HIV is the emergence of viral strains resistant to the drugs in use. Counteracting the emergence of resistance necessitates alternating the panel of agents employed. In order to rationally design alternative drug combinations, physicians not only must know the genotype of the emerging viral strains, but should also be able to correlate it with its resistant phenotype. However, resitant viral strains usually carry multiple mutations, whose reciprocal influences on the overall level of resistance are largely unknown.


We have focused our studies on the NNRTIs resistance mutations and their influence on the binding of both NNRTIs and NRTIs. A schematic drawing of the NNRTIs-binding site of HIV-1 RT with the most often mutated sidechains in green and the catalytically important residues in red is reproduced bel



By using a screening approach employing recombinant RT carrying the most commonly found drug resistance mutations, we have contributed to the identification of different novel classes of non-nucleoside RT inhibitors, some of which among the most potent currently known, with broad spectrum of activity also against drug resistant mutants. These compounds were developed in collaboration with the groups of Prof. Romano Silvestri, Antonello Mai and Roberto Di Santo of the University of Rome, La Sapienza; Prof. Maurizio Botta and Giuseppe Campiani of the University of Siena; Prof. Alba Chimirri of the University of Messina.


In addition, we have uncovered novel mechanisms of action of some of these compounds. In particular, in collaboration with the medicinal chemistry group of Prf. Maurizio Botta at the University of Siena. we have characterized the first nucleotide-competitive NNRTI (DAVP-1) and we have elucidated its mechanism of action thanks to the resolution of the crystal structure of this compound in complex with HV-1 RT (in collabroation with Dr. Eric Ennifar of the CNRS-University of Strasbourg, France), showing that it binds to a site different from all other known RT inhibitors.



Selected References


Rotili D, Samuele A, Tarantino D, Ragno R, Musmuca I, Ballante F, Botta G, Morera L, Pierini M, Cirilli R, Nawrozkij MB, Gonzalez E, Clotet B, Artico M, Esté JA, Maga G, Mai A. 2-(Alkyl/aryl)amino-6-benzylpyrimidin-4(3H)-ones as inhibitors of wild-type and mutant HIV-1: enantioselectivity studies. J Med Chem. 2012 Apr 12;55(7):3558-62.

Samuele A, Bisi S, Kataropoulou A, La Regina G, Piscitelli F, Gatti V, Silvestri R, Maga G. Mechanism of interaction of novel indolylarylsulfone derivatives with K103N and Y181I mutant HIV-1 reverse transcriptase in complex with its substrates. Antivir Chem Chemother. 2011 Nov 17;22(3):107-18.


Butini S, Gemma S, Brindisi M, Borrelli G, Fiorini I, Samuele A, Karytinos A,  Facchini M, Lossani A, Zanoli S, Campiani G, Novellino E, Focher F, Maga G. Enantioselective binding of second generation pyrrolobenzoxazepinones to the catalytic ternary complex of HIV-1 RT wild-type and L100I and K103N drug resistant mutants. Bioorg Med Chem Lett. 2011 Jul 1;21(13):3935-8. 


Maga G, Radi M, Gerard MA, Botta M, Ennifar E. HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate. Viruses. 2010 Apr;2(4):880-99. 


Samuele A, Crespan E, Vitellaro S, Monforte AM, Logoteta P, Chimirri A, Maga G. Slow binding-tight binding interaction between benzimidazol-2-one inhibitors and HIV-1 reverse transcriptase containing the lysine 103 to asparagine mutation. Antiviral Res. 2010 Jun;86(3):268-75.


Freisz S, Bec G, Radi M, Wolff P, Crespan E, Angeli L, Dumas P, Maga G, Botta  M, Ennifar E. Crystal structure of HIV-1 reverse transcriptase bound to a non-nucleoside inhibitor with a novel mechanism of action. Angew Chem Int Ed Engl. 2010 Mar 1;49(10):1805-8.&nb


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