A key issue in the development of novel HIV drugs is their ability to inhibit the replication of genetically diverse isolates, especially those isolates from the most globally prevalent subtypes, A, B, and C. Therefore, the antiviral efficacy of the newly developed compounds was evaluated in a standardized PBMC-based anti-HIV-1 assay with a panel of HIV-1 clinical isolates from different geographic locations that included HIV-1 group M subtypes A, B, C, D, E , F, and G, as well as HIV-1 group O. The panel included CCR5-tropic (R5), CXCR4-tropic (X4), and dual-tropic (R5X4) viruses. As summarized on Fig, the hit compounds inhibited the replication of viruses from all group M subtypes (A, B, C, and D, E, F and G), and also the group O isolate. The compound acts against all the virus types (the variation of the activity is about 0.5 log units, which is marginally significant).
Hit optimization program
We optimize the hit compounds to achieve better in-vitro activity and improve the medicinal chemistry profile. We use all the available computational tools to select the chemical modifications of the first generation MA binders, checking the in-vitro efficacy and cytoxocity levels. The last generation of the MA protein inhibitors has been recently tested at InPheno (CH). The top molecules, code named D2, C2, E1, and G1 were studied at 2uM in the so called deCIPhR assay to assess the efficacy with respect to the virus replication levels. The compound D2 suppressed the virus replication by a more than 60% margin. The chemically close substancies, C2, E1 and G1 demonstrated intermediate results (the virus replication inhibition more than 30% though less than 60%).
Another direction of the optimization is to improve the pharamako-dynamics properties. The in-vivo studies were performed in Toxicology Institute (Russia). PO PK parameters indicate fair plasma protein binding, good bioavailability (~30%), t1/2 = 4h. Since no signs of toxicity has ever been observed in the experiments, further optimization will mainly focus on the efficacy and pharmacokinetics.
The Company has considerable experience in developing drug candidates acting on the matrix proteins of viruses. In particular, by analogy with the HIV virus, we developed and are conducting tests on molecules acting on the M1 matrix protein of the influenza virus (the functional analogue of the HIV virus protein p17/MA). Accumulated data from our studies in vitro and in vivo confirms the high efficiency and the low toxicity of medicines (drugs) acting on matrix proteins. This lets us claim with the confidence that the proposed HIV inhibitors will provide a good therapeutic and commercial value on the market of drugs against HIV/AIDS.