8G1W

Crystal Structure Matriptase (C731S) in Complex with Inhibitor VD4162B

Summary for 8G1W

• Entry DOI: 10.2210/pdb8g1w/pdb
• Descriptor: Suppressor of tumorigenicity 14 protein, Cyclic peptide inhibitor (ACE)Y(DTR)(NLE)(THZ), Cyclic peptide inhibitor (ACE)Y(DTR)(NLE)(KCM), ... (5 entities in total)
• Functional Keywords: matriptase, inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 28045.06

Authors

Lovell, S.,Kashipathy, M.M.,Battaile, K.P.,Janetka, J.W. (deposition date: 2023-02-03, release date: 2024-02-07, Last modification date: 2024-04-10)

Primary citation

Damalanka, V.C.,Banas, V.,De Bona, P.,Kashipathy, M.M.,Battaile, K.,Lovell, S.,Janetka, J.W.
Mechanism-Based Macrocyclic Inhibitors of Serine Proteases.
J.Med.Chem., 67:4833-4854, 2024

PubMed Abstract: Protease inhibitor drug discovery is challenged by the lack of cellular and oral permeability, selectivity, metabolic stability, and rapid clearance of peptides. Here, we describe the rational design, synthesis, and evaluation of peptidomimetic side-chain-cyclized macrocycles which we converted into covalent serine protease inhibitors with the addition of an electrophilic ketone warhead. We have identified potent and selective inhibitors of TMPRSS2, matriptase, hepsin, and HGFA and demonstrated their improved protease selectivity, metabolic stability, and pharmacokinetic (PK) properties. We obtained an X-ray crystal structure of phenyl ether-cyclized tripeptide VD4162 () bound to matriptase, revealing an unexpected binding conformation. Cyclic biphenyl ether VD5123 () displayed the best PK properties in mice with a half-life of 4.5 h and compound exposure beyond 24 h. These new cyclic tripeptide scaffolds can be used as easily modifiable templates providing a new strategy to overcoming the obstacles presented by linear acyclic peptides in protease inhibitor drug discovery.

PubMed: 38477709
DOI: 10.1021/acs.jmedchem.3c02388

Experimental method

X-RAY DIFFRACTION (1.2 Å)