Newly Synthesized HIV-1 Protease Inhibitors

Abstract from Fourth National Congress of Virology with International Participation /Days of Virology in Bulgaria Sofia, May 18th - 20th, 2016

Radka Argirova, Ilia Manolov, Stancho Stanchev, Fabio Benedetti, Federico Berti, Vassil Atanassov

Department of Virology, National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria

Faculty of Pharmacy, Medical University, Sofia, Bulgaria

Department of Chemical and Pharmaceutical Sciences and Department of Life Sciences, University of Trieste, Italy

Faculty of Chemistry and Pharmacy, University of Sofia “St. Kliment Ohridsky”, Sofia, Bulgaria

Protease inhibitors (PIs) are an important part of Highly Active Antiretroviral Therapy (HAART). Because of drug resistance due to mutant viral strains the need still exists for development of new and efficient PIs. During the last five years our efforts were focused on evaluation of newly synthesized PIs belonging to two groups – the Ist group were peptidomimetics (four compounds based on Phe-Pro and Pro-Pro Dihydroxyethylene Isoesters) and the 2nd group consisted of non-peptidomimetics (six 4-hydroxycoumarine derivatives). The PIs were synthesized and verified in Trieste, Italy and Sofia, Bulgaria, respectively.

All newly synthesized PIs were biologically tested in MT-2/MT4 cells for inhibiting HIV-1IIIB replication by microtiter infection assay exploring the protection of cells from the cytopathic effect of HIV-1measured by cell survival in MTT test. Targeting further the activity of the compounds, endogenous and exogenous reverse transcriptase (RT) activity were found negative. Anti-PR activity was evaluated by a modified method for detection of PR activity using native viral enzyme instead of recombinant one. Then, molecular docking calculations and X-ray crystal structures of complexes PR-inhibitors were performed.

The newly synthesized PIs showed IC50 in nanomolar concentrations. In conclusion, two of the new PIs could be further chosen as pharmacophores to develop novel HIV-1 PIs.