HIPS-Talk: “In the quest for novel antivirals: From HIV-1 to HTLV-1 protease inhibitors“
With the discovery of Human T-cell leukemia virus-1 (HTLV-1) in 1980 and of HIV-1 in 1983, the existence of human retroviruses was confirmed. Since then, infections with the HI virus, which inevitably lead to the development of AIDS, evolved to a pandemic and are still among the most serious global health problems. In the last 30 years, potent drugs targeting various stages in the viral life cycle have been approved. However, the low fidelity of the viral reverse transcriptase and the fast replication rate are the main driving factors for the high mutation rate of the HI virus thus leading to an extensive resistance development and diminished efficacy of several clinically used drugs. The approved HIV protease inhibitors are in particular prone to cross-resistance due to their overall similar binding mode. Therefore, the development of new inhibitors preferably showing no susceptibility against resistant HIV protease strains is of utmost importance. In a rational, structure-based approach, a new class of pyrrolidine-based inhibitors exhibiting a deviating and, up to now, unique binding mode was developed. Interestingly, these inhibitors retain or even increase affinity towards an active site mutation.
Infections with HTLV-1 cause in severe cases the development of e.g. adult T-cell leukemia. In contrast to infections with HIV, no specific treatment options are currently available. Like HIV, HTLV-1 encodes an aspartic protease, which is essential for its maturation. Although this protease is very similar to the related HIV-1 protease (HIV-1 PR) with respect to the overall protein fold, their substrate specificity and inhibition profile differ significantly from each other. As a consequence, approved HIV-1 PR inhibitors show only a strongly reduced affinity against the HTLV-1 PR, thus hampering their clinical use. For the marketed HIV-1 PR inhibitor indinavir as well as for pyrrolidine-based inhibitors, X-ray structures in complex with HTLV-1 PR were determined providing valuable insights into their binding modes thus facilitating the further structure-guided inhibitor design for HTLV-1.
Gebäude und Raum
Blg E8.1, Conference Room (Ground floor)
Prof. Dr. Wibke Diederich
Department of Medicinal Chemistry, Philipps-Universität Marburg
Wibke Diederich obtained her Ph.D. in Medicinal Chemistry in 1999 from Philipps-Universität Marburg. She then moved to Kansas University, USA, working as a DFG-fellow in Prof. Dr. Gunda I. Georg’s laboratory on the total synthesis of salicylihalamides. In 2002, she returned to Marburg starting her independent research career. In 2009, she declined an offer from Christian-Albrechts-Universität zu Kiel and was appointed as full professor for Medicinal Chemistry in 2010 at Philipps-Universität Marburg. Since 2014, she also heads the Core Facility of Medicinal Chemistry at the Center for Tumor Biology and Immunology. Her research spans from the structure-based design and synthesis of inhibitors of viral and parasitic proteases to the ligand-based optimization of modulators of the nuclear receptor PPARβ/δ.
Prof. Dr. Rolf Hartmann