Kunitz domain-containing proteins are ubiquitous serine protease inhibitors with promising therapeutic potential. They target key proteases involved in major cellular processes such as inflammation or hemostasis through competitive inhibition in a substrate-like manner. Protease inhibitors from the Kunitz superfamily have a low molecular weight (18-24 kDa) and are characterized by the presence of one or more Kunitz motifs consisting of α-helices and antiparallel β-sheets stabilized by three disulfide bonds. Kunitz-type inhibitors are an important fraction of the protease inhibitors found in tick saliva. Their roles in inhibiting and/or suppressing host homeostatic responses continue to be shown to be additive or synergistic with other protease inhibitors such as cystatins or serpins, ultimately mediating successful blood feeding for the tick. In this review, we discuss the biochemical features of tick salivary Kunitz-type protease inhibitors. We focus on their various effects on host hemostasis and immunity at the molecular and cellular level and their potential therapeutic applications. In doing so, we highlight that their pharmacological properties can be exploited for the development of novel therapies and vaccines.

Laboratory of Experimental Immunology Department of Immunology Institute of Biomedical Sciences University of Sao Paulo Sao Paulo 05508 000 SP Brazil

Laboratory of Genomics and Proteomics of Disease Vectors Institute of Parasitology Biology Centre Czech Academy of Sciences 37005 Ceske Budejovice Czech Republic

Laboratory of Hematophagous Arthropods Department of Parasitology Federal University of Minas Gerais Belo Horizonte 31270 901 MG Brazil

National Institute of Science and Technology in Molecular Entomology National Council for Scientific and Technological Development Rio de Janeiro 21941 902 RJ Brazil

Tick Pathogen Transmission Unit Laboratory of Bacteriology Rocky Mountain Laboratories National Institute of Allergy and Infectious Diseases National Institutes of Health Hamilton MT 59840 USA

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Genome sequences of four Ixodes species expands understanding of tick evolution

Tick cysteine protease inhibitors suppress immune responses in mannan-induced psoriasis-like inflammation

Editorial: Special Issue on the "Molecular Biology of Disease Vectors"