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Unleashing the Therapeutic Potential of Human Kallikrein-Related Serine Proteases

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Unleashing the Therapeutic Potential of Human Kallikrein-Related Serine Proteases REVIEWS Unleashing the therapeutic potential of human kallikrein-related serine proteases Ioannis Prassas1,2*, Azza Eissa1,2*, Gennadiy Poda3,4 and Eleftherios P. Diamandis1,2 Abstract | Tissue kallikreins are a family of fifteen secreted serine proteases encoded by the largest protease gene cluster in the human genome. In the past decade, substantial progress has been made in characterizing the natural substrates, endogenous inhibitors and in vivo functions of kallikreins, and studies have delineated important pathophysiological roles for these proteases in a variety of tissues. Thus, kallikreins are now considered attractive targets for the development of novel therapeutics for airway, cardiovascular, tooth, brain, skin and neoplastic diseases. In this Review, we discuss recent advances in our understanding of the physiological functions and pathological implications of kallikrein proteases and highlight progress in the identification of kallikrein inhibitors, which together are bringing us closer to therapeutically targeting kallikreins in selected disease settings. proteases Proteases The majority of human serine known to date immune-like properties, thus modifying the originally Enzymes that break down the remain poorly characterized with regard to their natu- static view of them as redundant extracellular-matrix- peptide bonds that link amino ral substrates, inhibitors and in vivo functions, and so degrading enzymes6. KLK proteases are now known to acids together in proteins and only a few proteases — such as thrombin and factor Xa be involved in mechanistic pathways that regulate kid- polypeptides in a process in the blood coagulation cascade — have entered the ney function, skin desquamation, tooth enamel formation, known as proteolysis; they are 1 seminal liquefaction also known as peptidases, pharmaceutical drug development arena . Among the , synaptic neural plasticity and brain 7–9 proteolytic enzymes or relatively new, and not yet as extensively examined, ser- function . proteinases. ine proteases are members of the human tissue kallikrein In parallel, the importance of maintaining tight regu- (KLK) family2. This family encompasses human tissue lation of KLK activity in vivo has also become apparent. 1Department of Pathology kallikrein (KLK1) and 14 kallikrein-related peptidases Endogenous KLK activity is fine-tuned by several tissue- and Laboratory Medicine, (KLK2–KLK15). These fifteen homologous serine pro- specific regulatory mechanisms and factors, including Mount Sinai Hospital, Toronto, M5G 1X5, Canada. teases are encoded by the largest protease gene cluster zymogen (also known as pro-enzyme) activation cascades; 3 2Department of Clinical in the human genome . Traditionally, the KLK family endogenous KLK inhibitors (such as serpins, macroglobu- Biochemistry, University was known for the role of KLK1 in the kallikrein–kinin lins and the serine protease inhibitor lympho-epithelial Health Network, Toronto, system, and for the clinical applicability of KLK3 as a Kazal-type-related inhibitor 5 (LEKTI; encoded by the M5G 2C4, Canada. 4,5 3 prostate cancer screening biomarker . Much less was gene SPINK5)); [Au:OK?] micro-environmental pH; Drug Discovery Program, 2+ 10 Ontario Institute for Cancer understood about the remaining KLKs and their roles and single-metal-ion inhibitors of KLKs (such as Zn ) , Research, Toronto, in normal physiology and disease. among others. Disruption of the balanced tissue-specific M5G 0A3, Canada. However, over the past decade we have witnessed regulation of KLK activity has been linked to several 4Leslie Dan Faculty of great advances in our understanding of the tissue and pathologies, including respiratory diseases, neurodegen- Pharmacy, University of Toronto, Toronto, cellular localization, regulation and in vivo physiologi- eration, anxiety, schizophrenia, skin-barrier dysfunction, M5S 3M2, Canada. cal (and pathophysiological) functions of most KLKs. pathological inflammation and cancer. These associations *These authors contributed Notable functional insights have emerged following the have triggered numerous pharmacological efforts towards equally to this work. development of animal models with selectively modified the development of KLK-specific inhibitors as therapeu- Correspondence to E.P.D. KLKs (or endogenous inhibitors of KLKs) and with the tic agents11,12. As discussed below, these efforts have been e-mail: [email protected] identification of individuals with natural KLK deficien- further catalysed by the recent characterizations of the [Au: E-mail address OK?] cies. Collectively, these studies have characterized KLKs 3D crystal structures of KLKs and the elucidation of their doi:10.1038/nrd4534 as regulatory proteases with key signalling and innate preferred-substrate specificities. NATURE REVIEWS | DRUG DISCOVERY VOLUME 14 | MARCH 2015 | 1 REVIEWS In this Review, we summarize the progress that has catalytic triad. The hydroxyl group of this serine attacks been made in recent years in determining the biologi- the carbonyl carbon of the scissile peptide bond of the cal roles and therapeutic implications of tissue KLKs in substrate, resulting in the activation, inactivation or selected disease settings. We describe the current arsenal degradation of the substrate. KLK proteases exhibit of KLK inhibitors and conclude with emerging opportu- trypsin-like, chymotrysin-like or dual (tryptic and chy- nities and challenges associated with future development motryptic) activity. The interaction between the S1 site of KLK-based therapeutics. of a KLK and the P1 site of its substrate (using Schechter and Berger interaction nomenclature) is an important Human tissue kallikreins: digesting the basics determinant of the potency and specificity of each The term ‘kallikrein’ was first introduced in the 1930s KLK–substrate pair16. by Werle and colleagues to describe a kinin-generating Several techniques have been applied to characterize Skin desquamation substance in the human pancreas (which is known as the preferred prime-side and non-prime-side substrate The physiological peeling or ‘kallikreas’ in Greek)13. Since then, several KLK-like pro- specificities of individual KLKs, including phage display shedding of the outermost corneocytes of the skin. teases have been identified and are now classified into (which has been used to characterize KLK1–KLK3, 25–29 A typical cycle of skin two groups: plasma KLK (also known as KLK1B) and KLK6 and KLK14) , positional scanning of synthetic desquamation (which the tissue KLK family (KLK1–KLK15). Plasma KLK is combinatorial libraries (PS-SCL; used for KLK3–KLK7, takes ~14 days) involves the a liver-derived protease with a genomic localization and KLK10, KLK11, KLK13 and KLK14)30–33 and pep- apical movement and terminal differentiation of skin structural conformation that is unrelated to those of the tide screening (used for KLK1–KLK3, KLK6, KLK8 14–16 34–41 keratinocytes into corneocytes tissue KLKs . Although there has been substantial and KLK12–KLK14) . As shown in Supplementary and their eventual shedding pharmacological interest in plasma KLK (which was information S2 (table), trypsin-like KLKs (that is, KLK2, after cleavage by highlighted by the regulatory approval of ecallantide KLK4–KLK6, KLK8 and KLK11–KLK14) predomi- skin-associated proteases. (Kalbitor; Dyax) as a plasma-KLK-inhibiting drug in nantly cleave the peptide bond when the carboxyl side 17,18 Seminal liquefaction hereditary angioedema in the United States) , this of the amide bond at the P1 position of the substrate The enzymatic breakdown of Review will focus solely on the emerging therapeutic is a positively charged residue, such as in arginine or the seminal gel — formed by potential of tissue KLKs (KLK1–KLK15). For more lysine. By contrast, chymotrypsin-like KLKs (namely, proteins from the seminal on the therapeutic aspects of plasma KLK, readers are KLK3 and KLK7) cleave amide bonds that carry a large vesicles — to become more REFS 4,14,19,20 liquefied. A typical seminal referred to the reviews in . aromatic residue — such as that in tyrosine, tryptophan liquefaction cycle is completed Tissue KLKs belong to the chymotrypsin- and or phenylalanine — at the P1 position. This substrate within 20 minutes following trypsin-like serine endopeptidase family S1 (also specificity is rationalized by the level of shape- and ejaculation. known as clan PA [Au:OK? Or ‘part of the clan PA’ ? ] ) charge-complementarity between the P1 side-chain branch of the human protease family tree3,13 (FIG. 1a). of the substrate peptide and the S1 binding pocket of Catalytic triad The three conserved Approximately 80% of the 178 known human serine the enzyme. 21 amino-acid residues that are at proteases belong to the S1 family . In addition to the Notably, a conserved aspartic acid (Asp189) is the centre of the active sites of KLKs, this family also encompasses major proteases located deep inside the S1 pocket of most tryptic KLKs many enzymes (for example, such as thrombin, trypsin, chymotrypsin, elastase and (although KLK15 contains a glutamic acid, Glu189, here proteases, amidases, esterases 22 and lipases) and synergistically matriptase (MEROPS Peptidases database) . instead). The carboxylate moiety of this Asp189 forms account for their activity. All 15 genes that encode the KLKs colocalize in a strong ionic bond with either the positively-charged a tandem cluster on the long arm of chromosome 19 guanidine moiety of P1 arginine or the alkylamine moi- Prime side (19q13.3–19q13.4) and share
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