Targeting the kallikrein-related peptidases for drug development

Kallikrein-related peptidases (KLKs) constitute a family of 15 serine proteases. Recent studies have shed light on key physiological functions of KLK enzymes and implicate their deregulation in major human pathologies such as neurodegenerative and inflammatory diseases, skin conditions, asthma, and cancer. Consequently, KLKs have emerged as novel targets for pharmacological intervention. Given the pleiotropic roles of KLKs, both activators and inhibitors of KLK activities are of therapeutic interest. For example, inhibitors of hyperactive KLKs in the epidermis would be effective against excess skin desquamation and inflammation, whereas KLK activators could benefit hyperkeratosis caused by diminished KLK proteolysis. Expression of active KLKs by cancer cells and tissues can be exploited to target prodrugs that are proteolytically cleaved to release a cytotoxic compound or a cytolytic toxin at the site of KLK protease activity. Here, we review current approaches for the design and testing of KLK-based therapeutics. Kallikrein-related peptidases (KLKs) constitute a family of 15 serine proteases. Recent studies have shed light on key physiological functions of KLK enzymes and implicate their deregulation in major human pathologies such as neurodegenerative and inflammatory diseases, skin conditions, asthma, and cancer. Consequently, KLKs have emerged as novel targets for pharmacological intervention. Given the pleiotropic roles of KLKs, both activators and inhibitors of KLK activities are of therapeutic interest. For example, inhibitors of hyperactive KLKs in the epidermis would be effective against excess skin desquamation and inflammation, whereas KLK activators could benefit hyperkeratosis caused by diminished KLK proteolysis. Expression of active KLKs by cancer cells and tissues can be exploited to target prodrugs that are proteolytically cleaved to release a cytotoxic compound or a cytolytic toxin at the site of KLK protease activity. Here, we review current approaches for the design and testing of KLK-based therapeutics. synthetic oligonucleotides (RNA or DNA) that specifically recognize and bind to a target molecule that can be protein, peptide, or LMW compound. natural proteins or peptides that can be engineered to yield specific enzyme inhibitors. α1-Antichymotrypsin (ACT) and the cyclic peptide sunflower trypsin inhibitor (SFTI) have been exploited. peptides able to translocate through the plasma cell membrane to deliver their cargo inside the cell. Cargos can vary from small molecules, peptides, proteins, and nucleic acids to nanoparticles. a peptide with at least one ester linkage in place of an amide bond. Such peptides are found in natural sources such as bacteria, fungi, and marine organisms. fully automated, robotic screening techniques using compounds selected on the basis of structural information about a given receptor or natural ligand and biochemical tests (e.g., enzyme inhibition assays, sensitive ligand-binding assays) to identify active compounds (e.g., enzyme inhibitors). HTS allows bioassays (in microtiter plates) of thousands of compounds (library) in multiple assays at the same time. proteins encoded by the KNG1 gene, which is alternatively spliced to yield two transcripts that are translated to either low- or high-molecular-weight kininogen, which is involved in blood coagulation. in vitro screening technique that uses bacteriophages to identify biomolecular interactions. Each peptide or protein sequence is displayed on the surface of a filamentous bacteriophage. Engineered phages are then bound to the immobilized molecular target, and phages with high-binding affinity can be isolated by repeated cycles of phage selection, washing, and elution. small family of four (PAR1–4) G-protein-coupled receptors proteolytically activated by serine proteases to transmit intracellular signals. application of phage display to the identification of protease substrates. Phages displaying peptide sequences are bound to an affinity support (often through a His tag) and then treated with a protease. If a peptide is a substrate for the protease, then cleavage and release of the phage occur. Phages released from the solid support are collected and subjected to repeated rounds of selection to identify highly specific substrates. computational technique used in drug discovery. It involves a quick search of libraries with chemical structures against a biologically active target.