Publication: Interacciones proteína-proteína como diana terapéutica en la transcriptasa interna del VIH-1 y en la tripanotión reductasa de "leishmania infantum"
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2013-06-24
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Universidad Complutense de Madrid
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Abstract
In the last years, special attention has been given to protein-protein interactions (PPIs) in the field of drug discovery. Organisms are highly regulated by a complex
and diverse net of PPIs, which allow them to adapt or to interact adequately to the environment. Indeed, the molecular basis of a large variety of disorders is due to
abolished, disrupted or not well established PPIs. However, some handicaps like the protein-protein interface topology as well as the need of more powerful techniques have limited until very recently the growth of PPIs as chemotherapeutic
targets in the pharmaceutical sciences. On the contrary, in the last years an increasing number of new and potent molecules as PPIs modulators have already reached clinical phases. Between different approximations, finding out those residues that have a significant contribution to the overall protein-protein interaction energy in multimeric complexes, has emerged as a useful tool in the development of PPIs modulators. The identification of these residues, named hot spots, has been validated as a good starting point within a rational design in Medicinal Chemistry. As result of previous theoretical and experimental studies, our research group and collaborators identified two hot spots at dimer interfaces of both HIV-1 reverse transcriptase (HIV-1 RT, heterodimer) and L. infantum reverse transcriptase (Li-
TryR, homodimer) as essential elements for their imerization and catalytic stability: the 7/8 loop of the HIV-1 RT p51 subunit and the residue Glu436 (located in -helix of Li-TryR). These enzymes are essential for the survival of both
the virus and the parasite. The former catalyzes the key step of the reverse transcription of the viral RNA to DNA; the later keeps an optimal redox metabolism for the parasite. As proof of concept, different peptides were designed and evaluated as PPIs inhibitors. Among them, 1.12 (Ac-cyclo1,6[CINNEC]-NH2) and 2.01 (Ac-
PEIIQSVGISMKM-NH2) were able of inhibit, in the micromolar range, the dimerization process of HIV-1 reverse transcriptase and L. infantum, respectively. These results provide an excellent onset in the search of new inhibitors...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica I, leída el 26-04-2013