Viral Protease Inhibitors

Abstract

This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HIV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HIV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is limited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufficiently ubiquitous that treating an acute infection would be beneficial even if the infection was ultimately self-limiting. Protease inhibitor development is most advanced for hepatitis C virus (HCV), and we also provide a review of HCV NS3/4A serine protease inhibitor development, including combination therapy and resistance. Finally, we discuss other viral proteases as potential drug targets, including those from Dengue virus, cytomegalovirus, rhinovirus, and coronavirus.

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma

“…Consistent with this idea is the fact that treatment of isolated primary human T cells and T-cell lines with saturating concentrations of the MALT1 inhibitor reproducibly led to partial (Ϸ40-60%) inhibition of cytokine production (10). Proteases control many vital functions directly related to human health, and selective pharmacological inhibition of proteases has become a strategy for the rational therapy of diseases including cardiovascular disorders (28), neurodegeneration (29), osteoporosis, and bone metastasis (30) and viral infections (31). Interestingly, inhibitors of the proteasome have emerged as effective drugs for the treatment of multiple myeloma and mantle cell lymphoma (32), and a recent study has shown that the proteasome inhibitor bortezomib enhances the activity of chemotherapy in relapsed or refractory forms of ABC but not GCB DLBCL (33).…”

Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance

“…HIV-1 protease inhibitors (PIs) have played a critical role in the success of highly active antiretroviral therapy (HAART) (1)(2)(3). PIs are the key drugs in 2 of the 4 recommended initial HAART regimens and are also extremely important in salvage therapy for patients who fail initial regimens (1).…”

Kinetic and Thermodynamic Analysis of Dimerization Inhibitors Binding to HIV Protease Monomers by Surface Plasmon Resonance

“…Внедрение в клиническую практику 9 конкурентных ингибиторов протеазы ВИЧ (пВИЧ) явилось существенным прогрессом в лечении СПИДа [1,2]. Оценка энтальпии и энтропии образования молекулярных комплексов с помощью методов поверхностного плазмонного резонанса и изотермического калориметрического титрования внесли заметный вклад в разработку более эффективных конкурентных ингибиторов и их прототипов [3][4][5][6][7][8].…”