Protease inhibitors (PIs) are ubiquitous regulatory proteins present in all kingdoms. They play crucial tasks in controlling biological processes directed by proteases which, if not tightly regulated, can damage the host organism. PIs can be classified according to their targeted proteases or their mechanism of action. The functions of many PIs have now been characterized and are showing clinical relevance for the treatment of human diseases such as arthritis, hepatitis, cancer, AIDS, and cardiovascular diseases, amongst others. Other PIs have potential use in agriculture as insecticides, anti-fungal, and antibacterial agents. PIs from tick salivary glands are special due to their pharmacological properties and their high specificity, selectivity, and affinity to their target proteases at the tick-host interface. In this review, we discuss the structure and function of PIs in general and those PI superfamilies abundant in tick salivary glands to illustrate their possible practical applications. In doing so, we describe tick salivary PIs that are showing promise as drug candidates, highlighting the most promising ones tested in vivo and which are now progressing to preclinical and clinical trials.

Faculty of Science University of South Bohemia in České Budějovice 37005 České Budějovice Czech Republic

Innovation and Development Laboratory Innovation and Development Center Instituto Butantan São Paulo 05503 900 Brazil

Institut Pasteur de Tunis Université de Tunis El Manar LR19IPTX Service d'Entomologie Médicale Tunis 1002 Tunisia

Laboratory of Genomics and Proteomics of Disease Vectors Biology Centre CAS Institute of Parasitology Branišovská 1160 31 37005 České Budějovice Czech Republic

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