Last update 19 Sep 2024

HGFA

Last update 19 Sep 2024

Basic Info

Synonyms

Hepatocyte growth factor activator, Hepatocyte growth factor activator long chain, Hepatocyte growth factor activator short chain

+ [4]

Introduction

Activates hepatocyte growth factor (HGF) by converting it from a single chain to a heterodimeric form.

Drugs associated with HGFA

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

Caramcillin

Target

HGFA x hepsin x matriptase

Mechanism

HGFA inhibitors [+2]

Active Org.-

Originator Org.-

Active Indication-

Inactive Indication

Bacterial Infections

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with HGFA

100 Translational Medicine associated with HGFA

0 Patents (Medical) associated with HGFA

293

Literatures (Medical) associated with HGFA

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

01 Apr 2024·Macromolecular Bioscience

Bacteriophage Engineering for Improved Copper Ion Binding

Article

Author: Baik, Seungyun ; Himawan, Sandiego ; Usman, Muhammed ; Kim, Minyoung ; Korkmaz, Nuriye

AbstractIn this study, fd viruses are genetically modified to display seven cropped versions (H, HG, HGF, HGFA, HGFAN, HGFANV and HGFANVA) of the previously identified Cu(II) specific peptide (HGFANVA). Atomic force microscopy (AFM) imaging reveals the typical filamentous structures of recombinant phages with thicknesses of ≈2–5 nm in dry state. Scanning electron microscopy (SEM) imaging shows that HGFANVA viruses form larger elongated assemblies than H viruses that are deposited with a mineral layer after Cu(II) treatment. C and N peaks are detected for virus samples through Energy dispersive X‐ray spectroscopy (EDX) analyses confirming the presence of phage organic material. Cu peak is only detected for engineered viruses after Cu(II) exposure. Enzyme‐linked immunosorbent assay (ELISA) analyses show the selective Cu(II) binding of engineered phages. Agarose gel electrophoresis (AGE) and zeta potential analyses reveal negative surface charges of engineered viral constructs. Positively charged Cytopore beads are coated with bacteriophages and used for Cu(II) ion sorption studies. ICP‐MS analyses clearly show the improved Cu(II) binding of engineered viruses with respect to wild‐type fd phages. Such bottom‐up constructed, genetically engineered virus‐based biomaterials may be applied in bioremediation studies targeting metal species from environmental samples.

28 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Mechanism-Based Macrocyclic Inhibitors of Serine Proteases

Q1 · MEDICINE

Article

Author: Kashipathy, Maithri M ; De Bona, Paolo ; Janetka, James W ; Lovell, Scott ; Banas, Victoria ; Damalanka, Vishnu C ; Battaile, Kevin

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 (8b) bound to matriptase, revealing an unexpected binding conformation. Cyclic biphenyl ether VD5123 (11) 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.

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HGFA

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