FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3092617816> ?p ?o ?g. }

• W3092617816 endingPage "521" @default.
• W3092617816 startingPage "510" @default.
• W3092617816 abstract "Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clinically for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clinical efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (<i>k</i>_inact/K_I) of 1.5 × 10⁴ M⁻¹s⁻¹. High-resolution liquid chromatography-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 hours. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 Å, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptin-deficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clinically relevant efficacy. <h3>SIGNIFICANCE STATEMENT</h3> Interest in targeted covalent drugs has expanded in recent years, particularly so for kinase targets, but also more broadly. This study demonstrates that reversible covalent inhibition of the serine protease enteropeptidase is a therapeutically viable approach to the treatment of metabolic diseases and that mechanistic details of inhibition are relevant to clinical efficacy. Our mechanistic and kinetic studies outline a framework for detailed inhibitor characterization that is proving essential in guiding discovery efforts in this area." @default.
• W3092617816 created "2020-10-15" @default.
• W3092617816 creator A5005866769 @default.
• W3092617816 creator A5022261026 @default.
• W3092617816 creator A5031416424 @default.
• W3092617816 creator A5031445686 @default.
• W3092617816 creator A5039740102 @default.
• W3092617816 creator A5044622632 @default.
• W3092617816 creator A5045371685 @default.
• W3092617816 creator A5050047134 @default.
• W3092617816 creator A5051374276 @default.
• W3092617816 creator A5062929535 @default.
• W3092617816 creator A5073060347 @default.
• W3092617816 creator A5090812559 @default.
• W3092617816 date "2020-10-08" @default.
• W3092617816 modified "2023-10-01" @default.
• W3092617816 title "Targeting Enteropeptidase with Reversible Covalent Inhibitors To Achieve Metabolic Benefits" @default.
• W3092617816 cites W1540882827 @default.
• W3092617816 cites W1985469117 @default.
• W3092617816 cites W1989351796 @default.
• W3092617816 cites W1995985664 @default.
• W3092617816 cites W2008780832 @default.
• W3092617816 cites W2014028746 @default.
• W3092617816 cites W2019436999 @default.
• W3092617816 cites W2058570645 @default.
• W3092617816 cites W2060906363 @default.
• W3092617816 cites W2064979212 @default.
• W3092617816 cites W2075502795 @default.
• W3092617816 cites W2081830944 @default.
• W3092617816 cites W2108921801 @default.
• W3092617816 cites W2124026197 @default.
• W3092617816 cites W2146080841 @default.
• W3092617816 cites W2147874841 @default.
• W3092617816 cites W2158586590 @default.
• W3092617816 cites W2159211495 @default.
• W3092617816 cites W2295296898 @default.
• W3092617816 cites W2331364727 @default.
• W3092617816 cites W2886851907 @default.
• W3092617816 cites W2917868259 @default.
• W3092617816 cites W2947651472 @default.
• W3092617816 cites W2967289321 @default.
• W3092617816 cites W2972277754 @default.
• W3092617816 doi "https://doi.org/10.1124/jpet.120.000219" @default.
• W3092617816 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33033171" @default.
• W3092617816 hasPublicationYear "2020" @default.
• W3092617816 type Work @default.
• W3092617816 sameAs 3092617816 @default.
• W3092617816 citedByCount "17" @default.
• W3092617816 countsByYear W30926178162020 @default.
• W3092617816 countsByYear W30926178162021 @default.
• W3092617816 countsByYear W30926178162022 @default.
• W3092617816 countsByYear W30926178162023 @default.
• W3092617816 crossrefType "journal-article" @default.
• W3092617816 hasAuthorship W3092617816A5005866769 @default.
• W3092617816 hasAuthorship W3092617816A5022261026 @default.
• W3092617816 hasAuthorship W3092617816A5031416424 @default.
• W3092617816 hasAuthorship W3092617816A5031445686 @default.
• W3092617816 hasAuthorship W3092617816A5039740102 @default.
• W3092617816 hasAuthorship W3092617816A5044622632 @default.
• W3092617816 hasAuthorship W3092617816A5045371685 @default.
• W3092617816 hasAuthorship W3092617816A5050047134 @default.
• W3092617816 hasAuthorship W3092617816A5051374276 @default.
• W3092617816 hasAuthorship W3092617816A5062929535 @default.
• W3092617816 hasAuthorship W3092617816A5073060347 @default.
• W3092617816 hasAuthorship W3092617816A5090812559 @default.
• W3092617816 hasBestOaLocation W30926178161 @default.
• W3092617816 hasConcept C178790620 @default.
• W3092617816 hasConcept C180577832 @default.
• W3092617816 hasConcept C181199279 @default.
• W3092617816 hasConcept C182220744 @default.
• W3092617816 hasConcept C185592680 @default.
• W3092617816 hasConcept C202751555 @default.
• W3092617816 hasConcept C2776414213 @default.
• W3092617816 hasConcept C2776568683 @default.
• W3092617816 hasConcept C2776714187 @default.
• W3092617816 hasConcept C2776980637 @default.
• W3092617816 hasConcept C2777807008 @default.
• W3092617816 hasConcept C2909000736 @default.
• W3092617816 hasConcept C55493867 @default.
• W3092617816 hasConcept C57992300 @default.
• W3092617816 hasConcept C71240020 @default.
• W3092617816 hasConceptScore W3092617816C178790620 @default.
• W3092617816 hasConceptScore W3092617816C180577832 @default.
• W3092617816 hasConceptScore W3092617816C181199279 @default.
• W3092617816 hasConceptScore W3092617816C182220744 @default.
• W3092617816 hasConceptScore W3092617816C185592680 @default.
• W3092617816 hasConceptScore W3092617816C202751555 @default.
• W3092617816 hasConceptScore W3092617816C2776414213 @default.
• W3092617816 hasConceptScore W3092617816C2776568683 @default.
• W3092617816 hasConceptScore W3092617816C2776714187 @default.
• W3092617816 hasConceptScore W3092617816C2776980637 @default.
• W3092617816 hasConceptScore W3092617816C2777807008 @default.
• W3092617816 hasConceptScore W3092617816C2909000736 @default.
• W3092617816 hasConceptScore W3092617816C55493867 @default.
• W3092617816 hasConceptScore W3092617816C57992300 @default.
• W3092617816 hasConceptScore W3092617816C71240020 @default.
• W3092617816 hasIssue "3" @default.
• W3092617816 hasLocation W30926178161 @default.

• next