The primary objective of this project is to develop innovative small-molecules useful as therapeutic tool for the treatment and prevention of HIV/AIDS.
The innovative aspect of this strategy is that targeted activity is the relatively unexplored reverse transcriptase (RT)-associated ribonuclease H (RNase H) function, which selectively degrades the RNA of the RNA-DNA hybrid produced by the retrotranscription process.
The primary objective will be reached through the development of compounds with selective inhibiting activity against RNase H domain of HIV-1 RT enzyme.
This group has already identified: i) a class of diketo acids that inhibits both HIV-1 RNase H and IN activities; ii) compounds binding to a novel RT site that are able to selectively inhibit RT-associated RNase H, iii) amino acid residues within the catalytic core of RNase H interacting with the inhibitos. This is a strong base for rational drug design of specific Rnase H inhibitors.
The competitive advantage of this proposal is based on original chemistry and modelling driving development of new drugs targeting HIV-1 RNase H. It is the goal of this project to have at least one HIV-1 RNase H inhibitor into a later stage of preclinical development. To date, no RNase H inhibitors are in clinical trial.
The present project proposal fully meets these requirements given that:
i) it is promoting the formation of a new network of an academic, which will bring together expertises from different disciplines
(chemistry, structural biology, biochemistry, virology) and will be devoted to effectively translate basic knowledge into a preclinical application;
ii) it is focused on the development of a validated attractive target, which has been very little explored in the last 20 years and, hence, it is considered as a new HIV-1 target: the RT-associated RNase H function;
iii) it is focused on the identification of new hit/lead compounds that can be turned into new anti-HIV drugs through a preclinicaldevelopment.
At the moment, it is not clear whether the HIV-1 RT-associated RNase H function can be considered a target that can be inhibited bycompounds with broad anti-HIV spectrum given that no inhibitor of the enzyme function has never reached an advancedstage of preclinical development. However, the present project proposal will verify this possibility by testing the identifiedhits/leads against a wide variety of clinical isolates, comprising multi-drug resistant strains. However, it is worth to note that our hit compound RDS1643 was active also on some HIV-1 drug resistant strains.
Given this context, the present project proposal will contribute to the international efforts, which address the global health HIV/AIDS problem. In fact, the development of new HIV/AIDS drugs targeted to the HIV-1 RT-associated RNase H function is certainly an priority focus in the development of new therapies.