Design and synthesis of new hybrid latency reversal agents for HIV treatment

Background: HIV latency reservoir remains one of the main barriers to eliminate the virus. The “kick-and-kill” strategy aims to reactivate the HIV latency reservoir in the first step “kick” and the elimination of these reactivated virus in the second step, “kill”. Latency-reversing agents such as histone deacetylase (HDAC) and bromodomain (BRD-4) inhibitors have been described in “kick-and-kill” strategy to reactivate HIV reservoirs. Here, we described the design, preparation and evaluation of hybrid compounds designed to target both BRD-4 and HDAC 1-3 simultaneously. Methods: In silico studies were performed using the molecular modelling Maestro by Schrödinger environment, using BRD-4 (pdb code: 4WIV) and HDAC-2 (pdb code: 4LY1). All compounds were prepared through divergent synthesis. First, it was performed a Suzuki coupling reaction between the methyl 4-iodobenzoate and boronic acid derivatives. The ester function was hydrolysed and the compound was coupled with o-phenylenediamine using EDC. The ability of the compounds (at 10 mM) to inhibit both HDAC 1-3 and BRD-4 were evaluated. Results: Docking simulation suggests that all compounds are able to interact with BRD-4 and HDAC-2. Five compounds were synthesized at global yields ranging from 11-20%. All structures were characterized by analytical methods. The most promising compound was able to inhibit HDAC 1-3 and BRD4 at values of 75 %, 72 %, 57 % and 21 %, respectively. Conclusions: Hybrid compounds were designed, synthesized and evaluated against the enzymes HDAC and BRD. These dual compounds were able to inhibit BRD-4 and HDAC 1-3 suggesting its potential use as latency-reversing agents.