Key Points
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Tissue kallikreins (KLKs) constitute a family of 15 secreted serine proteases that are encoded by the largest protease gene cluster in the human genome.
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KLKs were traditionally known for their clinical applicability as cancer markers — for instance, KLK3 (also known as prostate-specific antigen) is a marker for prostate cancer.
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The field of KLK research has recently blossomed with the development of KLK-knockout models and the elucidation of the 3D structures of several KLKs.
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Novel pathophysiological roles for these proteases have recently been assigned in various tissues, such as the airway, cardiovascular system, tooth, skin and brain tissues.
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The promise of KLKs as therapeutic targets in various pathologies — including skin diseases, hereditary angioedema, neurodegeneration, inflammation and cancer — is emerging.
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Systematic efforts for the development of the first generation of KLK-based inhibitors as candidate therapeutics have already been initiated.
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.
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Change history
28 August 2015
The references for compound 1 and compound 8 were incorrectly cited. The authors apologize for this unintended error, and the online version of the article has been corrected.
16 September 2015
The classes of compounds developed as KLK1 inhibitors mentioned on page 194 were modified.
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Acknowledgements
G.P. would like to acknowledge the support of the Ontario Institute for Cancer Research and its funding from the Government of Ontario, Canada.
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Supplementary information
Supplementary information S1 (table)
Summary of the % nucleotide sequence identities between KLK-related peptidases* (PDF 120 kb)
Supplementary information S2 (table)
Diagrammatic summary of the preferred substrate specificities of the human KLK peptidases according to the MEROPS Peptidase Database* (PDF 111 kb)
Supplementary information S3 (figure)
Structure of other major serine proteases in standard orientation. (PDF 375 kb)
Glossary
- Proteases
-
Enzymes that break down the peptide bonds that link amino acids together in proteins and polypeptides in a process known as proteolysis; they are also known as peptidases, proteolytic enzymes or proteinases.
- Skin desquamation
-
The physiological peeling or shedding of the outermost corneocytes of the skin. A typical cycle of skin desquamation (which takes ~14 days) involves the apical movement and terminal differentiation of skin keratinocytes into corneocytes and their eventual shedding after cleavage by skin-associated proteases.
- Seminal liquefaction
-
The enzymatic breakdown of the seminal gel — formed by proteins from the seminal vesicles — to become more liquefied. A typical seminal liquefaction cycle is completed within 20 minutes following ejaculation.
- Catalytic triad
-
The three conserved amino-acid residues that are at the centre of the active sites of many enzymes (for example, proteases, amidases, esterases and lipases) and synergistically account for their activity.
- Prime side
-
According to Schechter and Berger's nomenclature of interactions between protease active sites and peptidic or protein substrates, enzyme binding subsites (S′) and their corresponding substrate peptide (P′) residues that are C-terminal to the scissile peptide bond are termed 'prime side' and designated as S1′, S2′ and P1′, P2′, respectively.
- Phage display
-
A molecular laboratory technique for the production and screening of novel proteins or polypeptides. The desired gene fragment is expressed by bacteriophages, which display the resulting protein on their surface where it can be tested for biological activity or interactions with other proteins, peptides or DNA.
- Lamellar granules
-
Specialized secretory organelles typically found in keratinocytes and type 2 pneumocytes that are also known as membrane-coating granules, lamellar bodies, keratinosomes or Odland bodies. The keratinocyte trans-Golgi network and lamellar granules are parts of the same continuous membrane structure, in which lamellar granules transport their cargo and fuse with the cell membrane at the border of the stratum granulosum and stratum corneum to release their contents into the extracellular milieu.
- Acanthosis
-
An abnormal, diffuse hypertrophy of the stratum spinosum, as in eczema and psoriasis.
- Long-term potentiation
-
(LTP) The biological process behind the persistent increase and long-lasting enhancement in synaptic strength following electrical or chemical stimulation of neurons. It is a crucial cellular mechanism for both learning memory (also known as long-term memory) and working memory (also known as short-term memory).
- Chondromyces crocatus
-
A Gram-negative bacteria strain that belongs to the myxobacteria family. They live predominantly in the soil and feed on insoluble organic substances. Although they are poorly distributed ecologically, numerous secondary metabolite products of Chondromyces crocatus have been recently found.
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Prassas, I., Eissa, A., Poda, G. et al. Unleashing the therapeutic potential of human kallikrein-related serine proteases. Nat Rev Drug Discov 14, 183–202 (2015). https://doi.org/10.1038/nrd4534
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DOI: https://doi.org/10.1038/nrd4534
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