RESUMO
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.
RESUMO
Non-coding RNAs (ncRNAs) are nucleotide sequences that are known to assume regulatory roles previously thought to be reserved for proteins. Their functions include the regulation of protein activity and localization and the organization of subcellular structures. Sequencing studies have now identified thousands of ncRNAs encoded within the prokaryotic and eukaryotic genomes, leading to advances in several fields including parasitology. ncRNAs play major roles in several aspects of vector–host–pathogen interactions. Arthropod vector ncRNAs are secreted through extracellular vesicles into vertebrate hosts to counteract host defense systems and ensure arthropod survival. Conversely, hosts can use specific ncRNAs as one of several strategies to overcome arthropod vector invasion. In addition, pathogens transmitted through vector saliva into vertebrate hosts also possess ncRNAs thought to contribute to their pathogenicity. Recent studies have addressed ncRNAs in vectors or vertebrate hosts, with relatively few studies investigating the role of ncRNAs derived from pathogens and their involvement in establishing infections, especially in the context of vector-borne diseases. This Review summarizes recent data focusing on pathogen-derived ncRNAs and their role in modulating the cellular responses that favor pathogen survival in the vertebrate host and the arthropod vector, as well as host ncRNAs that interact with vector-borne pathogens.
RESUMO
Immunodeficiency disorders and autoimmune diseases are common, but a lack of effective targeted drugs and the side-effects of existing drugs have stimulated interest in finding therapeutic alternatives. Naturally derived substances are a recognized source of novel drugs, and tick saliva is increasingly recognized as a rich source of bioactive molecules with specific functions. Ticks use their saliva to overcome the innate and adaptive host immune systems. Their saliva is a rich cocktail of molecules including proteins, peptides, lipid derivatives, and recently discovered non-coding RNAs that inhibit or modulate vertebrate immune reactions. A number of tick saliva and/or salivary gland molecules have been characterized and shown to be promising candidates for drug development for vertebrate immune diseases. However, further validation of these molecules at the molecular, cellular, and organism levels is now required to progress lead candidates to clinical testing. In this paper, we review the data on the immuno-pharmacological aspects of tick salivary compounds characterized in vitro and/or in vivo and present recent findings on non-coding RNAs that might be exploitable as immunomodulatory therapies.