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Unleashing the therapeutic potential of human kallikrein-related serine proteases

Published on Mar 1, 2015in Nature Reviews Drug Discovery57.62
· DOI :10.1038/nrd4534
Ioannis Prassas13
Estimated H-index: 13
,
Azza Eissa5
Estimated H-index: 5
+ 1 AuthorsEleftherios P. Diamandis97
Estimated H-index: 97
Cite
Abstract
Members of the family of kallikrein (KLK)-related proteases are found in various tissues — including the airway, prostate and brain — and have a wide range of functions. The authors describe the roles of KLKs in health and disease, and highlight the small-molecule, peptide-based, protein-based, antibody-based and immunotherapeutic strategies that are being used to target KLKs in certain diseases.
  • References (229)
  • Citations (92)
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References229
Newest
Published on Sep 19, 2014in PLOS ONE2.78
Johanna M. Mattsson7
Estimated H-index: 7
(HYKS: Helsinki University Central Hospital),
Suvi Ravela1
Estimated H-index: 1
(HYKS: Helsinki University Central Hospital)
+ 5 AuthorsHannu Koistinen34
Estimated H-index: 34
(HYKS: Helsinki University Central Hospital)
Prostate-specific antigen (PSA or kallikrein-related peptidase-3, KLK3) exerts chymotrypsin-like proteolytic activity. The main biological function of PSA is the liquefaction of the clot formed after ejaculation by cleavage of semenogelins I and II in seminal fluid. PSA also cleaves several other substrates, which may explain its putative functions in prostate cancer and its antiangiogenic activity. We compared the proteolytic efficiency of PSA towards several protein and peptide substrates and ...
Published on Sep 1, 2014in Cancer and Metastasis Reviews6.67
Michael T. Schweizer15
Estimated H-index: 15
(Johns Hopkins University),
Charles G. Drake57
Estimated H-index: 57
(Johns Hopkins University)
Since the approval of sipuleucel-T for men with metastatic castrate resistant prostate cancer in 2010, great strides in the development of anti-cancer immunotherapies have been made. Current drug development in this area has focused primarily on antigen-specific (i.e. cancer vaccines and antibody based therapies) or checkpoint inhibitor therapies, with the checkpoint inhibitors perhaps gaining the most attention as of late. Indeed, drugs blocking the inhibitory signal generated by the engagement...
Published on Jul 1, 2014in Experimental Dermatology2.87
Shirley Wang4
Estimated H-index: 4
(Novartis),
Sabine Olt1
Estimated H-index: 1
(Novartis)
+ 3 AuthorsBarbara Wolff-Winiski4
Estimated H-index: 4
(Novartis)
Netherton syndrome (NS; OMIM 256500) is a genetic skin disease resulting from defects in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the protease inhibitor lympho-epithelial Kazal type inhibitor (LEKTI). We established a SPINK5 knockdown skin model by transfecting SPINK5 small interfering RNA (siRNA) into normal human epidermal keratinocytes, which were used together with fibroblast-populated collagen gels to generate organotypic skin cultures. This model recapitulate...
Published on May 1, 2014in Journal of Investigative Dermatology6.29
Jan A. Fischer49
Estimated H-index: 49
,
Zhihong Wu10
Estimated H-index: 10
+ 10 AuthorsKarina Reiss35
Estimated H-index: 35
The proteolytic regulation of the desquamation process by kallikrein-related peptidases (KLKs) is crucial for epidermal barrier function, and elevated KLK levels have been reported in atopic dermatitis. KLKs are controlled by specific inhibitors of the serine protease inhibitor of Kazal-type (Spink) family. Recently, SPINK6 was shown to be present in human stratum corneum. In order to investigate its role in epidermal barrier function, we studied mouse Spink6. Sequence alignment revealed that th...
Published on Jan 1, 2014in Methods of Molecular Biology
Hannu Koistinen34
Estimated H-index: 34
(HYKS: Helsinki University Central Hospital),
Can Hekim8
Estimated H-index: 8
(HYKS: Helsinki University Central Hospital)
+ 2 AuthorsUlf-Håkan Stenman72
Estimated H-index: 72
(HYKS: Helsinki University Central Hospital)
Published on Dec 1, 2013in European Journal of Medicinal Chemistry4.83
Xiao Tan3
Estimated H-index: 3
(UPMC: Pierre-and-Marie-Curie University),
Claudia Bertonati1
Estimated H-index: 1
(Paris Diderot University)
+ 5 AuthorsBruno O. Villoutreix41
Estimated H-index: 41
(Paris Diderot University)
Abstract Netherton syndrome is caused by loss-of-function mutations in SPINK5 encoding the Kazal-type inhibitor LEKTI-1 leading to dysregulation of proteolytic cascades involving several kallikreins. We used both structure-based and ligand-based virtual screening computations to identify commercially available non-covalent inhibitors of human kallikrein 5 (hK5), a serine protease (trypsin-like) that plays a central role in the initiation of the molecular cascades leading to the Netherton syndrom...
Published on Nov 20, 2013in PLOS ONE2.78
Andrew Cho12
Estimated H-index: 12
(NIH: National Institutes of Health),
Naoto Haruyama17
Estimated H-index: 17
(Tokyo Medical and Dental University)
+ 8 AuthorsCarolyn W. Gibson30
Estimated H-index: 30
(UPenn: University of Pennsylvania)
Transforming growth factor-s (TGF-s) signaling plays an important role in regulating crucial biological processes such as cell proliferation, differentiation, apoptosis, and extracellular matrix remodeling. Many of these processes are also an integral part of amelogenesis. In order to delineate a precise role of TGF-s signaling during amelogenesis, we developed a transgenic mouse line that harbors bovine amelogenin promoter-driven Cre recombinase, and bred this line with TGF-s receptor II floxed...
Published on Oct 1, 2013in Journal of The American Academy of Dermatology7.10
Alvin Coda7
Estimated H-index: 7
(UCSD: University of California, San Diego),
Tissa Hata24
Estimated H-index: 24
(UCSD: University of California, San Diego)
+ 8 AuthorsDel Rosso J23
Estimated H-index: 23
Background Excess cathelicidin and kallikrein 5 (KLK5) have been hypothesized to play a role in the pathophysiology of rosacea. Objective We sought to evaluate the effects of azelaic acid (AzA) on these elements of the innate immune system. Methods Gene expression and protease activity were measured in laboratory models and patients with rosacea during a 16-week multicenter, prospective, open-label study of 15% AzA gel. Results AzA directly inhibited KLK5 in cultured keratinocytes and gene expre...
Agnieszka Markowska4
Estimated H-index: 4
(UMB: Medical University of Białystok),
Magdalena Bruzgo2
Estimated H-index: 2
(UMB: Medical University of Białystok)
+ 1 AuthorsArkadiusz Surażyński18
Estimated H-index: 18
(UMB: Medical University of Białystok)
Tripeptides of the general X-SO2-d-Ser-AA-Arg-CO-Y formula, where X = α-tolyl, p-tolyl, 2,4,6-triisopropylphenyl; AA = alanine, glycine, norvaline and Y = OH, NH-(CH2)5NH2 were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. The most active compound towards urokinase was PhCH2SO2-d-Ser-Gly-Arg-OH with Ki value 5.4 μM and the most active compound toward thrombin was PhCH2SO2-d-Ser-NVa-Arg-OH with Ki value 0.82 μM. Th...
Published on Aug 1, 2013in Bioorganic & Medicinal Chemistry Letters2.45
Xiao Tan3
Estimated H-index: 3
(UPMC: Pierre-and-Marie-Curie University),
Laetitia Furio3
Estimated H-index: 3
(Paris V: Paris Descartes University)
+ 3 AuthorsChahrazade El Amri6
Estimated H-index: 6
(UPMC: Pierre-and-Marie-Curie University)
Abstract We describe here 1,2,4-triazoles derivatives identified as transient inactivators acting at the nanomolar level on human kallikreins (hK5, hK7 and hK14) and matriptase. Both the nature of the targeted enzymes and structural variations of the inhibitors influence the life-times of acyl-enzymes. These nonpeptidic, transient and low-molecular-weight inhibitors were found to be noncytotoxic against healthy human keratinocytes. These molecules may be useful to counteract dysregulated proteol...
Cited By92
Newest
Published on Dec 4, 2019in Artificial Cells Nanomedicine and Biotechnology4.46
Meiyin Zhang (HMU: Harbin Medical University), Bairong Xia1
Estimated H-index: 1
(HMU: Harbin Medical University)
+ 3 AuthorsGe Lou17
Estimated H-index: 17
(HMU: Harbin Medical University)
Published on Dec 1, 2019in BMC Cancer2.93
Weiwei Gong (TUM: Technische Universität München), Yueyang Liu1
Estimated H-index: 1
(TUM: Technische Universität München)
+ 6 AuthorsJulia Dorn14
Estimated H-index: 14
(TUM: Technische Universität München)
Background In ovarian cancer, dysregulation of mRNA expression of several components of the family of the kallikrein-related peptidases (KLKs) is observed. In this study, we have analyzed the KLK5 mRNA expression pattern in tumor tissue of patients suffering from high-grade serous ovarian cancer stage FIGO III/IV. Moreover, we have correlated the KLK5 mRNA levels with clinical outcome.
Published on Dec 1, 2019in Translational neurodegeneration
Oliver Goldhardt1
Estimated H-index: 1
(TUM: Technische Universität München),
Inanna Warnhoff (TUM: Technische Universität München)+ 7 AuthorsTimo Grimmer31
Estimated H-index: 31
(TUM: Technische Universität München)
Alterations in the expression of human kallikrein-related peptidases (KLKs) have been described in patients with Alzheimer’s disease (AD). We elucidated the suitability of KLK6, KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers. KLK levels in cerebrospinal fluid (CSF), as determined by ELISA, were compared between 32 AD patients stratified to A/T/(N) system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers. Ass...
Published on Oct 1, 2019in Molecular Immunology3.06
Kristina Nilsson-Ekdahl38
Estimated H-index: 38
(LNU: Linnaeus University),
Camilla Mohlin7
Estimated H-index: 7
(LNU: Linnaeus University)
+ 6 AuthorsBo Nilsson66
Estimated H-index: 66
Abstract In the alternative pathway (AP) an amplification loop is formed, which is strictly controlled by various fluid-phase and cell-bound regulators resulting in a state of homeostasis. Generation of the “C3b-like” C3(H2O) has been described as essential for AP activation, since it conveniently explains how the initial fluid-phase AP convertase of the amplification loop is generated. Also, the AP has a status of being an unspecific pathway despite thorough regulation at different surfaces. Du...
Published on Oct 1, 2019in Bioorganic & Medicinal Chemistry Letters2.45
Ann Louise Walker11
Estimated H-index: 11
(GSK: GlaxoSmithKline),
Alexis Denis8
Estimated H-index: 8
(GSK: GlaxoSmithKline)
+ 17 AuthorsMarie-Hélène Fouchet5
Estimated H-index: 5
(GSK: GlaxoSmithKline)
Abstract The connection between Netherton syndrome and overactivation of epidermal / dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and dev...
Published on Sep 12, 2019in Head and Neck Pathology
Zachary Kerr , Alyssa Hayter (UWO: University of Western Ontario)+ 1 AuthorsMark R. Darling13
Estimated H-index: 13
(UWO: University of Western Ontario)
Kallikrein-related peptidases (KLKs) are a group of 15 serine proteases implicated in a variety of biological processes. Aberrant expression of KLKs has been associated with the development of certain cancers. However, the role of KLKs in salivary tumors has not been extensively studied. This study evaluated the expression of KLKs in both adenoid cystic carcinoma (ACC) and normal salivary gland tissue. We isolated total RNA from 39 formalin-fixed, paraffin-embedded samples, which included 24 ACC...
Published on Sep 5, 2019in bioRxiv
David J. Forsthoefel (OMRF: Oklahoma Medical Research Foundation), Nicholas I Cejda (OMRF: Oklahoma Medical Research Foundation)+ 1 AuthorsPhillip A Newmark (Morgridge Institute for Research)
Organ regeneration requires precise coordination of new cell differentiation and remodeling of uninjured tissue to faithfully re-establish organ morphology and function. An atlas of gene expression and cell types in the uninjured state is therefore an essential pre-requisite for understanding how damage is repaired. Here, we use laser-capture microdissection (LCM) and RNA-Seq to define the transcriptome of the intestine of Schmidtea mediterranea, a planarian flatworm with exceptional regenerativ...
Published on Sep 1, 2019in Biochimie3.36
Peter Goettig16
Estimated H-index: 16
(University of Salzburg),
Hans Brandstetter30
Estimated H-index: 30
(University of Salzburg),
Viktor Magdolen38
Estimated H-index: 38
(TUM: Technische Universität München)
Abstract Trypsin and chymotrypsin-like serine proteases from family S1 (clan PA) constitute the largest protease group in humans and more generally in vertebrates. The prototypes chymotrypsin, trypsin and elastase represent simple digestive proteases in the gut, where they cleave nearly any protein. Multidomain trypsin-like proteases are key players in the tightly controlled blood coagulation and complement systems, as well as related proteases that are secreted from diverse immune cells. Some s...
Published on Aug 17, 2018in Head and Neck Pathology
Matthew D. Morrison (London Health Sciences Centre), Linda Jackson-Boeters10
Estimated H-index: 10
(UWO: University of Western Ontario)
+ 5 AuthorsMark R. Darling13
Estimated H-index: 13
(UWO: University of Western Ontario)
Pleomorphic adenoma (PA) is the most common benign salivary gland tumor. Kallikrein-related peptidases have been identified as biomarkers in many human tumors and may influence tumor behavior. We investigated KLK1−15 messenger ribonucleic acid and proteins in PA specimens to determine a KLK expression profile for this tumor. Fresh frozen PA tissue specimens (n = 26) and matched controls were subjected to quantitative real-time reverse transcription polymerase chain reaction to detect KLK1−15 mRN...
Tyler Lopez3
Estimated H-index: 3
(UCR: University of California, Riverside),
Zahid Mustafa1
Estimated H-index: 1
(UCR: University of California, Riverside)
+ 6 AuthorsXin Ge12
Estimated H-index: 12
(UCR: University of California, Riverside)
Critical for diverse biological processes, proteases represent one of the largest families of pharmaceutical targets. To inhibit pathogenic proteases with desired selectivity, monoclonal antibodies (mAbs) hold great promise as research tools and therapeutic agents. However, identification of mAbs with inhibitory functions is challenging because current antibody discovery methods rely on binding rather than inhibition. This study developed a highly efficient selection method for protease inhibito...
View next paperThe new human tissue kallikrein gene family: structure, function, and association to disease.