A5007324374- Viral gastroenteritis research and epidemiology
- Virus-based gene therapy research
- Viral Infections and Immunology Research
- Respiratory viral infections research
- Amino Acid Enzymes and Metabolism
- Animal Virus Infections Studies
- RNA and protein synthesis mechanisms
- RNA Interference and Gene Delivery
- Cytokine Signaling Pathways and Interactions
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Pharmacological Receptor Mechanisms and Effects
- Polyamine Metabolism and Applications
- Neuroinflammation and Neurodegeneration Mechanisms
- Lung Cancer Treatments and Mutations
- Neuroscience and Neuropharmacology Research
- Peptidase Inhibition and Analysis
- Melanoma and MAPK Pathways
- bioluminescence and chemiluminescence research
- Bacteriophages and microbial interactions
- Nuclear Receptors and Signaling
- Machine Learning in Materials Science
- GABA and Rice Research
- Clostridium difficile and Clostridium perfringens research
- Tryptophan and brain disorders
Indiana University – Purdue University Indianapolis
2023-2024
Indiana University School of Medicine
2024
Indiana University
2023
Northwestern University
2018-2023
Wichita State University
2012-2019
University of Colombo
2011
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in central nervous system. Inhibition of GABA aminotransferase (GABA-AT), a pyridoxal 5′-phosphate (PLP)-dependent enzyme that degrades GABA, has been established as possible strategy for treatment substance abuse. The raised levels occur consequence this inhibition have found to antagonize rapid release dopamine ventral striatum (nucleus accumbens) follows an acute challenge by addictive substance. In addition, increased...
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....
Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate-dependent enzyme, plays critical role in the progression of hepatocellular carcinoma (HCC). Pharmacological selective inhibition hOAT has been shown to be potential therapeutic approach for HCC. Inspired by discovery nonselective inactivator (1R,3S,4S)-3-amino-4-fluoro cyclopentane-1-carboxylic acid (1), this work, we rationally designed, synthesized, and evaluated novel series fluorine-substituted cyclohexene analogues,...
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,...
Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.1]heptanol warhead is reported herein. The inactivation mechanism involves novel α-iminol rearrangement. synthesis the features an asymmetric intramolecular Mannich reaction, utilizing chiral sulfinamide. This study presents approach toward functionalized...
Human ornithine aminotransferase (hOAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that was recently found to play an important role in the metabolic reprogramming of hepatocellular carcinoma (HCC) via proline and glutamine pathways. The selective inhibition hOAT by compound 10 exhibited potent vivo antitumor activity. Inspired discovery inactivator (1S,3S)-3-amino-4-(difluoromethylene)cyclopentane-1-carboxylic acid (5), we rationally designed, synthesized, evaluated series...
Aminotransferases are pyridoxal 5'-phosphate-dependent enzymes that catalyze reversible transamination reactions between an amino acid and α-keto acid, playing a critical role in cellular nitrogen metabolism. It is evident γ-aminobutyric aminotransferase (GABA-AT), which balances the levels of inhibitory excitatory neurotransmitters, has emerged as promising therapeutic target for epilepsy cocaine addiction based on mechanism-based inactivators (MBIs). In this work, we established integrated...
((S)-3-Amino-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (OV329) is a recently discovered inactivator of γ-aminobutyric aminotransferase (GABA-AT), which has 10 times better inactivation efficiency than its predecessor, CPP-115, despite the only structural difference being an endocyclic double bond in OV329. Both compounds are mechanism-based enzyme inactivators (MBEIs), inactivate GABA-AT by similar mechanism. Here, combination variety computational chemistry tools and...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure, and current treatment options are very limited. Previously, we performed high-throughput screen to identify small molecules that inhibit protein aggregation caused by mutation in the gene encodes superoxide dismutase 1 (SOD1), which responsible for about 25% of familial ALS. This resulted three hit series compounds were optimized over several years give highly active mutant SOD1 ALS model. Here target two...
Human noroviruses are the primary cause of outbreaks acute gastroenteritis worldwide. The problem is further compounded by current lack norovirus-specific antivirals or vaccines. Noroviruses have a single-stranded, positive sense 7 to 8 kb RNA genome which encodes polyprotein precursor that processed virus-encoded 3C-like cysteine protease (NV 3CLpro) generate at least six mature nonstructural proteins. Processing essential for virus replication, consequently, NV 3CLpro has emerged as an...
Positive-sense RNA viruses, particularly those in the Picornavirus-like superfamily and Coronaviridae family, significantly impact public health, necessitating development of focused antiviral agents. The main proteases these viruses are promising targets for development. Peptidyl protease inhibitors containing Pro derivatives, mimicking rigid Leu at P2 position, have emerged as potent drug candidates against SARS-CoV-2 3CLpro, despite several theoretical disadvantages compared to non-Pro...
Abstract Background Lyn kinase, a member of the Src family tyrosine kinases, predominantly phosphorylates ITIM and ITAM motifs linked to immune receptors adaptor proteins, is emerging as target for Alzheimer’s disease (AD). The role in TREM2‐mediated microglial activation phagocytosis, critical pathway clearing Aβ plaques, remains unclear potent, selective, brain penetrant inhibitors are unavailable. In this study, we report characterization kinase from literature well establishment an...
Abstract Background The TREAT‐AD centers aim to improve Alzheimer’s Disease (AD) research by offering free, high‐quality tools and technologies. Lyn is a tyrosine kinase that belongs the Src family kinases. expression of its activity have been implicated in AD. This class proteins involved TREM2 mediated microglial activation phagocytosis, process which beneficial for clearing neurotoxins such as Aβ oligomers brain. inhibition may activate microglia. Given relationship between accumulation...
In the wake of pandemic, peptidyl protease inhibitors with Pro-based rigid Leu mimetics at P2 position have emerged as potent drug candidates against SARS-CoV-2 main protease. This success is intuitively attributed to enhanced hydrophobic interactions and rigidity in literature. However, tertiary amide proline derivatives, which hinders formation a critical hydrogen bond enzyme active site, constrained PPII conformation, contradicts preferred β-strand represent two overlooked disadvantages...
Positive-sense RNA viruses, particularly those in the Picornavirus-like superfamily and Coronaviridae family, significantly impact public health, necessitating development of focused antiviral agents. The main proteases these viruses are promising targets for development. Peptidyl protease inhibitors containing Pro derivatives, mimicking rigid Leu at P2 position, have emerged as potent drug candidates against SARS-CoV-2 3CLpro, despite several theoretical disadvantages compared to non-Pro...