A5079943962- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- Synthesis and biological activity
- Neuroinflammation and Neurodegeneration Mechanisms
- Liver physiology and pathology
- Cancer Mechanisms and Therapy
- Retinal Diseases and Treatments
- Protein Kinase Regulation and GTPase Signaling
- Diverse Scientific Research Studies
- Melanoma and MAPK Pathways
- Alzheimer's disease research and treatments
- Synthesis and bioactivity of alkaloids
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Drug Transport and Resistance Mechanisms
- Ion Transport and Channel Regulation
- Cholesterol and Lipid Metabolism
- Multicomponent Synthesis of Heterocycles
- SARS-CoV-2 detection and testing
- Synthesis and Biological Evaluation
- Synthesis of Tetrazole Derivatives
- Biochemical and Molecular Research
- Drug Solubulity and Delivery Systems
- Trypanosoma species research and implications
- Parasitic Diseases Research and Treatment
Washington University in St. Louis
2021-2025
Boston Children's Hospital
2020-2024
Georgetown University
2020
Pfizer (United States)
2007-2010
Office of Science
2005
University of Missouri–St. Louis
2005
Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through elimination of supernumerary synapses, have an established role in this process. While microglial receptor TREM2 soluble complement proteins C1q C3 are recognized as key players, neuronal molecular components that specify synapses to be eliminated still undefined. Here, we show exposed phosphatidylserine (PS) represents a "eat-me" signal involved microglial-mediated pruning. In...
A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated 2 (MAPKAP-K2 or MK-2) the treatment rheumatoid arthritis has been prepared and evaluated. These have IC50 values as low 10 nM against target good selectivity profiles a number kinases including CDK2, ERK, JNK, p38. MK-2 shown to suppress TNFα production in U397 cells be efficacious an acute inflammation model. The structure−activity relationships this series, their activity both vitro vivo models...
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...
We have discovered a novel class of nonsteroidal pyrazoline antagonists the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble had propensity to inhibit hERG channel. Remarkably, both these challenges overcome by incorporation single carboxylate moiety. Structural modification carboxylate-containing lead R-4g with wide range substituents at each position ring resulted in R-12o, which shows activity...
ABSTRACT We developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases, including transmembrane protease 2 (TMPRSS2), matriptase, and hepsin. TMPRSS2 is membrane-associated that highly expressed in the upper lower respiratory tracts utilized by SARS-CoV-2 other viruses to proteolytically process their glycoproteins, enabling entry, replication, dissemination new virus particles. have previously shown compound MM3122 exhibited subnanomolar potency...
Soil-transmitted helminth (STH) infections affect one-fourth of the global population and pose a significant threat to human animal health, with limited treatment options emerging drug resistance. Trichuris trichiura (whipworm) stands out as neglected disease, necessitating new drugs address this unmet medical need. We discovered that several different chemical series related Provirus Integration sites for Moloney murine leukemia virus (PIM) family kinase inhibitors possess potent...
TMPRSS2 is a membrane associated serine protease which important in the viral pathogenesis of coronaviruses and influenza viruses. We developed mechanism-based covalent α-ketobenzothiazole (kbt) inhibitors using established substrate specificity PS-SCL screening as rational guide for inhibitor design. Three distinct focused libraries tetrapeptide kbts were synthesized evaluated their inhibition TMPRSS2, matriptase other proteases. also investigated different capping groups previously...
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...
Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause mortality in Western society. We believe that by preventing reabsorption bile acids, minimally absorbed apical sodium-codependent acid transporter (ASBT) inhibitor would lower serum without potential systemic side effects an drug. A series novel benzothiepines...
In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since primary site for active reabsorption is via ASBT, which localized on luminal surface of distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects an absorbed drug. To ensure bioequivalency and product stability, it was also essential identify nonhygroscopic in its most stable...
Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce host for very long periods. To identify macrofilaricides, we carried out phenotypic screening a library 2121 approved clinical use against Brugia pahangi prioritized hits further studies...
Leukotriene B(4) (LTB(4)) is a potent, proinflammatory mediator involved in the pathogenesis of number diseases including inflammatory bowel disease, psoriasis, rheumatoid arthritis, and asthma. The enzyme LTA(4) hydrolase represents an attractive target for pharmacological intervention these disease states, since action this rate-limiting step production LTB(4). Our previous efforts focused on exploration series analogues related to screening hit SC-22716 (1,...
Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss dendrites. However, the mechanisms by which synapses are damaged not fully understood.Dendrite length and remodeling occurs via microtubules, dynamics regulated microtubule-binding proteins, including microtubule-associated protein 2 (MAP2). The HIV gp120 is neurotoxic interferes neuronal microtubules. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) immunoreactivity...
Abstract Neuronal circuits assembly requires the fine equilibrium between synapse formation and elimination. Microglia, through elimination of supernumerary synapses, have an established role in this process. While microglial receptor TREM2 soluble complement proteins C1q C3 are recognized key players process, neuronal molecular components that tag synapses to be eliminated still undefined. Here we show exposed phosphatidylserine (PS) represents a ‘eat-me’ signal enabling microglial-mediated...
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...
ABSTRACT We have developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases including transmembrane protease 2 (TMPRSS2), matriptase and hepsin. TMPRSS2 is membrane associated which highly expressed in the upper lower respiratory tract utilized by SARS-CoV-2 other viruses to proteolytically process their glycoproteins, enabling receptor binding, entry, replication, dissemination new virion particles. previously shown that compound MM3122 exhibited...
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 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,...