Last update 01 Nov 2024

hepsin

Last update 01 Nov 2024

Basic Info

Synonyms

hepsin, HPN, Serine protease hepsin

+ [5]

Introduction

Serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL (PubMed:21875933, PubMed:15839837). Plays a role in cell growth and maintenance of cell morphology (PubMed:8346233, PubMed:21875933). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Mediates the proteolytic cleavage of urinary UMOD that is required for UMOD polymerization (PubMed:26673890).

Drugs associated with hepsin

SRI 31215

Target

HGF x hepsin x matriptase

Mechanism

HGF stimulants [+2]

Active Org.

Southern Research Institute

Originator Org.

Southern Research Institute

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Caramcillin

Target

HGFA x hepsin x matriptase

Mechanism

HGFA inhibitors [+2]

Active Org.-

Originator Org.-

Active Indication

Bacterial Infections

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

VD-4162

Target

HGFA x TMPRSS2 x hepsin

Mechanism

HGFA inhibitors [+2]

Active Org.

Washington University School of Medicine

Originator Org.

Washington University School of Medicine

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with hepsin

100 Translational Medicine associated with hepsin

0 Patents (Medical) associated with hepsin

346

Literatures (Medical) associated with hepsin

01 Nov 2024·Hearing Research

Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: Insights from transgenic mouse models

Article

Author: Chung, Fong-Ling ; Pan, Jhih-Yu ; Hung, Chia-Jui ; Wu, Chen-Chi ; Lin, Shu-Wha ; Hsu, Yu-Chen ; Chen, Li-Fu ; Liu, Tien-Chen ; Tsai, Yu-Fei ; Fang, Mo-Chu ; Yang, Ting-Hua ; Yeh, Peng ; Yen, Alice Chih Chia ; Yu, Wei-Ming

Mutations in various type II transmembrane serine protease (TMPRSS) family members are associated with non-syndromic hearing loss, with some mechanisms still unclear. For instance, the mechanism underlying profound hearing loss and tectorial membrane (TM) malformations in hepsin/TMPRSS1 knockout (KO) mice remains elusive. In this study, we confirmed significantly elevated hearing thresholds and abnormal TM morphology in hepsin KO mice, characterized by enlarged TM with gaps and detachment from the spiral limbus. Transgenic mouse lines were created to express either wild-type or a serine protease-dead mutant of human hepsin in the KO background. The Tg68;KO line, expressing moderate levels of wild-type human hepsin in the cochlea, showed partial restoration of hearing function. Conversely, the Tg5;KO or TgRS;KO lines, with undetectable hepsin or protease-dead hepsin, did not show such improvement. Histological analyses revealed that Tg68;KO mice, but not Tg5;KO or TgRS;KO mice, had a more compact TM structure, partially attached to the spiral limbus. These results indicate that hepsin expression levels correlate with improvements in hearing and TM morphology, and its protease activity is critical for these effects. Hepsin's role was further examined by studying its relationship with α-tectorin (TECTA) and β-tectorin (TECTB), non-collagenous proteins crucial for TM formation. Hepsin was co-expressed with TECTA and TECTB in the developing cochlear epithelium. Immunostaining showed decreased levels of TECTA and TECTB in hepsin KO TM, partially restored in Tg68;KO mice. These findings suggest that hepsin is essential for proper TM morphogenesis and auditory function, potentially by proteolytic processing/maturation of TECTA and TECTB and their incorporation into the TM.

18 Sep 2024·Cell biology and toxicology

Hepsin as a potential therapeutic target for alleviating acetaminophen-induced hepatotoxicity via gap-junction regulation and oxidative stress modulation.

Article

Author: Lin, Shu-Wha ; Hsu, Yu-Chen ; Yu, I-Shing ; Hung, Chia-Lu ; Wu, Yao-Ming ; Fang, Mo-Chu ; Sheu, Jin-Chuan ; Chen, Chien-Hung ; Tsai, Yu-Fei

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury.

01 Aug 2024·Protein Science

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin

Article

Author: Damalanka, Vishnu C. ; Helander, Jonathan ; Poreba, Marcin ; Janetka, James W. ; Drag, Marcin ; De Bona, Paolo ; Kasperkiewicz, Paulina ; Lovell, Scott ; O'Donoghue, Anthony J. ; Kashipathy, Maithri M. ; Kooner, Anoopjit S. ; Mahoney, Matthew W. ; Battaile, Kevin P. ; Craik, Charles S. ; Rut, Wioletta ; Norman, Mariah

AbstractInhibition of the proteolytic processing of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for the drug discovery of novel anticancer therapeutics which prevent tumor progression and metastasis. Here, we utilized an improved and expanded version of positional scanning of substrate combinatorial libraries (PS‐SCL) technique called HyCoSuL to optimize peptidomimetic inhibitors of the HGF/MSP activating serine proteases, HGFA, matriptase, and hepsin. These inhibitors have an electrophilic ketone serine trapping warhead and thus form a reversible covalent bond to the protease. We demonstrate that by varying the P2, P3, and P4 positions of the inhibitor with unnatural amino acids based on the protease substrate preferences learned from HyCoSuL, we can predictably modify the potency and selectivity of the inhibitor. We identified the tetrapeptide JH‐1144 (8) as a single digit nM inhibitor of HGFA, matriptase and hepsin with excellent selectivity over Factor Xa and thrombin. These unnatural peptides have increased metabolic stability relative to natural peptides of similar structure. The tripeptide inhibitor PK‐1‐89 (2) has excellent pharmacokinetics in mice with good compound exposure out to 24 h. In addition, we obtained an X‐ray structure of the inhibitor MM1132 (15) bound to matriptase revealing an interesting binding conformation useful for future inhibitor design.

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hepsin

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