HIVREVDRUG

Descripción

HIV/AIDS remains one of the leading contributors to the global burden of disease, particularly in low- and middle-income countries. Current antiretroviral therapy can control human immunodeficiency virus type 1 (HIV-1) replication but is not curative due to persistent latent viral reservoirs. This situation is compounded by further drawbacks such as drug side effects, lack of adherence, drug resistance and economic challenges. Although alternative medical strategies are being explored to overcome these problems, none of them has been successful so far. In this context, the present proposal focuses on the discovery of small-molecules blocking the complex between the HIV-1 Rev protein and the Rev Recognition Element (RRE) in the viral RNA. This action precludes nuclear export of unspliced or singly-spliced viral transcripts, an essential step in the virus cycle that is not targeted by any of the currently marketed antiretroviral treatments. We propose to use an iterative approach based on data-based compound design, chemical syntheses, and in vitro and ex vivo experiments to optimize the therapeutic index of different classes of molecules previously shown to inhibit Rev function: terphenylene mimics of the RNA-binding a-helix of Rev with multi-target antiretroviral action, and several types of HIV RNA biogenesis inhibitors identified by monitoring the displacement of Rev from its high-affinity RRE site. We will likewise optimize the properties of allosteric compounds aimed to block Rev function by altering the three-dimensional arrangement of Rev sites in the RRE. The antiretroviral activity of the best compounds belonging to any of these classes will be determined using a humanized mouse model after assessing the pharmacokinetics and toxicity properties of selected inhibitors in vivo. By following this multidisciplinary approach, we expect to identify a lead compound with a novel action on HIV-1 RNA biogenesis, which may contribute to find the path towards complete HIV-1 remission.

Investigadores

Investigador Principal: José Gallego (Universidad Católica de Valencia)

Investigadores participantes:

• Saurabh Loharch, Mateusz Szewczyk, Cristina Medina, Ángela Moreno, Sergi Chumillas (Universidad Católica de Valencia)
• José Alcamí, Luis M. Bedoya (Instituto de Salud Carlos III, Madrid)
• Sergi Chumillas, Vicente Marchán (Universitat de Barcelona)
• Jon Izquierdo, Sara Morón, María C. Puertas, J. Martínez-Picado (Instituto Irsicaixa, Badalona)

Publicaciones relacionadas:

-Simba-Lahuasi, A.; Alcamí, J.; Beltrán, M., Bedoya, L.M. & Gallego, J. Novel HIV-1 RNA biogenesis inhibitors identified by virtual pharmacophore-based screening. Biochemical Pharmacology 215, 115734 (2023).

-Chumillas, S.; Loharch, S.; Beltrán, M.; Szewczyk, M.P.; Bernal, S.; Puertas, M.C.; Martinez-Picado, J.; Alcamí, J.; Bedoya, L.M.; Marchán, V.; Gallego, J. Exploring the HIV-1 Rev Recognition Element (RRE)-Rev Inhibitory Capacity and Antiretroviral Action of Benfluron Analogs. Molecules 28, 7031 (2023).

-Simba-Lahuasi, A.; Cantero-Camacho, A.; Rosales, R., McGovern, B.L.; Rodriguez, M.L.; Marchán, V.; White, K.M.; García-Sastre, A.; Gallego, J.et al. SARS-CoV-2 Inhibitors Identified by Phenotypic Analysis of a Collection of Viral RNA-Binding Molecules. Pharmaceuticals 15, 1448 (2022).

-Fang X; Gallego J; Wang YX. Deriving RNA topological structure from SAXS. Methods in enzymology 677, 479 (2022).