Cysteine Protease Inhibitors: from Evolutionary Relationships to Modern Chemotherapeutic Design for the Treatment of Infectious Diseases

E.      C.Y. Toh; N.      L. Huq; S.      G. Dashper; E.      C. Reynolds

Abstract

Cysteine proteases are one of the largest groups of proteases and are involved in many important biological functions in all kingdoms of life. They are virulence factors of a range of eukaryotic, bacterial and viral pathogens and are involved in host invasion, pathogen replication and disruption of the host immune response. Their activity is regulated by a range of protease inhibitors. This review discusses the various families of cysteine protease inhibitors, their different modes of inhibition and their evolutionary relationships. These inhibitors as well as the recent discovery of propeptide and propeptide-like inhibitors provide insights into the structures that are important for particular inhibitory mechanisms, thus forming the foundation for the design of future therapeutics.

Keywords: Cysteine proteases, cysteine protease inhibitors, therapeutics, infectious diseases, pathogen replication, immune response, evolutionary relationships, substrate specificity, nutrient acquisition, non-structural viral protein, Trypanosoma cruzi, Trypanosoma brucei, stefins, phytocystatins, factor aplha, interferon-γ-activated macrophages, nitric oxide, interleukin-10, β-immunoglobulin, proteolysis, BCPI