A5057991731- Viral gastroenteritis research and epidemiology
- Virus-based gene therapy research
- Liver physiology and pathology
- Viral Infections and Immunology Research
- Colorectal Cancer Treatments and Studies
- Respiratory viral infections research
- Hepatocellular Carcinoma Treatment and Prognosis
- Bacteriophages and microbial interactions
- SARS-CoV-2 and COVID-19 Research
- Click Chemistry and Applications
- Protein Kinase Regulation and GTPase Signaling
- COVID-19 Clinical Research Studies
- Pancreatic and Hepatic Oncology Research
- Phagocytosis and Immune Regulation
- PI3K/AKT/mTOR signaling in cancer
- Cancer Cells and Metastasis
- Fibroblast Growth Factor Research
- HER2/EGFR in Cancer Research
- HIV/AIDS drug development and treatment
- Carbohydrate Chemistry and Synthesis
- Galectins and Cancer Biology
- Escherichia coli research studies
- Biochemical and Molecular Research
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
Washington University in St. Louis
2018-2024
Wichita State University
2015-2018
The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses essential viral spread in lung. Utilizing rational structure-based design (SBDD) coupled to substrate specificity screening TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) inhibitors which are structurally distinct from significantly improved...
Abstract Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, most cancers, RTKs maintain moderate expression remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the for MET RON, HGF HGFL, respectively, are synthesized inactive precursors activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo...
Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for management norovirus infection. 3C-like protease is essential replication, consequently, inhibition this enzyme a fruitful avenue investigation that may lead to emergence antinorovirus therapeutics. We describe herein optimization dipeptidyl inhibitors using iterative SAR, X-ray crystallographic, and cell-based studies....
Pancreatic cancer (PC) is a deadly with high mortality rate. The unique characteristics of PC, including desmoplasia and immunosuppression, have made it difficult to develop effective treatment strategies. stellate cells (PSCs) play crucial role in the progression disease by interacting cells. One key mediators PSC - cell interactions hepatocyte growth factor (HGF)/c-MET pathway. Using an immunocompetent vivo model PC as well vitro experiments, this study has shown that combined approach...
Abstract Inhibition of the proteolytic processing hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for drug discovery novel anticancer therapeutics which prevent tumor progression metastasis. Here, we utilized improved expanded version positional scanning substrate combinatorial libraries (PS‐SCL) technique called HyCoSuL to optimize peptidomimetic inhibitors HGF/MSP activating serine proteases, HGFA, matriptase, hepsin. These have...
Matriptase and hepsin belong to the family of type II transmembrane serine proteases (TTSPs). Increased activity these plasma protease, hepatocyte growth factor activator (HGFA), is associated with unregulated cell signaling tumor progression through increased MET RON kinase pathways. These are highly expressed in multiple solid tumors hematological malignancies. Herein, we detail synthesis structure–activity relationships (SAR) a dipeptide library bearing Arg α-ketobenozothiazole (kbt)...
Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There currently no vaccines or small molecule therapeutics available for treatment prophylaxis norovirus infections. Norovirus 3CL protease plays vital role in viral replication by generating structural nonstructural proteins via cleavage polyprotein. Thus, molecules that inhibit may have potential therapeutic value. We describe herein structure-based design, synthesis,...
Protease inhibitor drug discovery is challenged by the lack of cellular and oral permeability, selectivity, metabolic stability, rapid clearance peptides. Here, we describe rational design, synthesis, evaluation peptidomimetic side-chain-cyclized macrocycles which converted into covalent serine protease inhibitors with addition an electrophilic ketone warhead. We have identified potent selective TMPRSS2, matriptase, hepsin, HGFA demonstrated their improved pharmacokinetic (PK) properties....
Hepatocyte growth factor (HGF), the ligand for MET receptor tyrosine kinase, is a tumor-promoting that abundant in tumor microenvironment. Proteolytic activation of inactive pro-HGF by one or more serine endopeptidases matriptase, hepsin, and HGF activator rate-limiting step HGF/MET signaling. Herein, we have rationally designed novel class side chain cyclized macrocyclic peptide inhibitors. The new series cyclic tripeptides has superior metabolic stability significantly improved...
A series of piperidine-based peptidomimetic inhibitors have been synthesized and evaluated their activity against the three serine proteases HGFA, matriptase, hepsin. All analogs showed nanomolar matriptase
Abstract The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This activates the Spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and other coronaviruses essential viral spread in lung. Utilizing rational structure-based design (SBDD) coupled to substrate specificity screening TMPRSS2, we have discovered a novel class small molecule ketobenzothiazole inhibitors with significantly improved activity over existing...
Abstract Using 3D type I collagen cultures of human colorectal cancer (CRC) cell line HCA-7 derivatives (CC, SC, CC-CR), we previously identified that activation receptor tyrosine kinases (RTKs) MET and RON contributed to resistance anti-EGFR monoclonal antibody, cetuximab. CC cells are sensitive cetuximab, while SC CC-CR resistant in 3D. Both de novo acquired modes cetuximab CC-CR, respectively, could be overcome by crizotinib, a multi-RTK inhibitor also targets RON. In fact, now show the...
Abstract Overproduction of Hepatocyte Growth Factor (HGF) in the tumor microenvironment by tumor-associated fibroblasts or cancer cells is associated with poor patient outcomes and a common cause therapeutic resistance. HGF signals via MET receptor, which results activation downstream signaling pathways that promote cell survival, proliferation, migration, scattering, invasion cells. secreted as an inactive precursor, pro-HGF, proteolytic processing into its active form one serine proteases,...