A5015465067- SARS-CoV-2 and COVID-19 Research
- Lipid Membrane Structure and Behavior
- Biofuel production and bioconversion
- Animal Virus Infections Studies
- Microbial Metabolites in Food Biotechnology
- Enzyme Production and Characterization
- Bacterial Genetics and Biotechnology
- RNA and protein synthesis mechanisms
- Viral gastroenteritis research and epidemiology
- Computational Drug Discovery Methods
- Virus-based gene therapy research
- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Infant Nutrition and Health
- RNA Interference and Gene Delivery
- Molecular Biology Techniques and Applications
- Protein Structure and Dynamics
- Respiratory viral infections research
- Peptidase Inhibition and Analysis
- Galectins and Cancer Biology
- Bacillus and Francisella bacterial research
- Cancer Immunotherapy and Biomarkers
- COVID-19 Clinical Research Studies
- Immunotherapy and Immune Responses
- Toxin Mechanisms and Immunotoxins
University of Alberta
2015-2025
Lomonosov Moscow State University
2003-2013
Louisiana State University Health Sciences Center New Orleans
2008
Abstract The main protease, M pro (or 3CL ) in SARS-CoV-2 is a viable drug target because of its essential role the cleavage virus polypeptide. Feline infectious peritonitis, fatal coronavirus infection cats, was successfully treated previously with prodrug GC376, dipeptide-based protease inhibitor. Here, we show and parent GC373, are effective inhibitors from both SARS-CoV IC 50 values nanomolar range. Crystal structures these have covalent modification nucleophilic Cys145. NMR analysis...
The main protease of SARS-CoV-2 (Mpro) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there a concern that mutations Mpro may alter structural and functional properties subsequently potency existing potential antivirals. We explored effect 31 belonging 5 (VOCs) on catalytic parameters substrate specificity, which revealed changes binding rate cleavage viral peptide. Crystal structures 11 mutants provided...
Abstract Blockade of the programmed cell death 1 (PD-1)/programmed death-ligand (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies individually disclosed several promising inhibitors, whose detailed experimental data are not publicly disclosed. this work, we report rigorous systematic vitro...
Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against broad spectrum of coronaviruses. Described in this Article novel α-acyloxymethylketone warhead peptidomimetic compounds with six-membered lactam glutamine mimic P1. Compounds potent SARS-CoV-2 3CL protease vitro viral replication inhibition were identified low cytotoxicity good plasma glutathione stability....
Parkinson's disease (PD) is a devastating neurodegenerative resulting from the death of dopaminergic neurons in substantia nigra pars compacta midbrain. Familial and sporadic forms have been linked to mitochondrial dysfunction. Pathology has identified with mutations PARK6 gene encoding PTEN-induced kinase 1 (PINK1), quality control protein mitochondria. Disease-associated at transmembrane region PINK1 were predicted disrupt cleavage by PARL protease inner membrane. Here, using microscopy,...
Abstract The COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. main protease (M pro ) is a viable drug target because of its essential role cleavage virus polypeptide subsequent viral replication. Feline infectious peritonitis, fatal infection cats caused by coronavirus, was successfully treated previously with dipeptide-based inhibitor. Here we show this drug, GC376, analog GC373,...
Tragically, the death toll from COVID-19 pandemic continues to rise, and with variants being observed around globe new therapeutics, particularly direct-acting antivirals that are easily administered, desperately needed. Studies targeting SARS-CoV-2 3CL protease, which is critical for viral replication, different peptidomimetics warheads an active area of research development potential drugs. To date, however, only a few publications have evaluated nitrile warhead as protease inhibitor,...
Coronaviruses infect a variety of hosts in the animal kingdom, and while each virus is taxonomically different, they all their host via same mechanism. The coronavirus main protease (Mpro, also called 3CLpro), an attractive target for drug development due to its essential role mediating viral replication transcription. An Mpro inhibitor, GC376, has been shown treat feline infectious peritonitis (FIP), fatal infection cats caused by internal mutations enteric (FECV). Recently, our lab...
Interferon (IFN)-stimulated gene 15 (ISG15) is a ubiquitin-like molecule that conjugates to target proteins via C-terminal LRLRGG motif and has antiviral function in vivo. We used structural modeling predict human ISG15 (hISG15) residues important for interacting with its E1 enzyme, UbE1L. Kinetic analysis revealed mutation of arginine 153 alanine (R153A) ablated hISG15-hUbE1L binding transthiolation UbcH8. Mutation other predicted UbE1L-interacting had minimal effects on the transfer from...
Proteolysis is an integral component of life and has been implicated in many disease processes. To improve our understanding peptidase function, it imperative to develop tools uncover substrate specificity cleavage efficiency. Here, we combine the quantitative power tandem mass tags (TMTs) with established peptide assay yield Multiplex Substrate Profiling by Mass Spectrometry (qMSP-MS). This was validated papain, a well-characterized cysteine peptidase, generate efficiency values for...
Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from USA Food Drug Administration (FDA) entered phase III clinical trials as a possible replacement Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (M
The rhomboid protease PARL is a critical regulator of mitochondrial homeostasis through its cleavage substrates such as PINK1, PGAM5, and Smac/Diablo, which have crucial roles in quality control apoptosis. However, the catalytic properties PARL, including effect lipids on protease, never been characterized vitro. To address this, we isolated human expressed yeast used FRET-based kinetic assays to measure proteolytic activity We show that detergent enhanced by cardiolipin, lipid enriched...
Pathogens have evolved a range of mechanisms to acquire iron from the host during infection. Several Gram-negative pathogens including members genera Neisseria and Moraxella two-component systems that can extract glycoproteins lactoferrin transferrin. The homologous iron-transport consist membrane-bound transporter an accessory lipoprotein. While mechanism behind acquisition transferrin is well understood, relatively little known regarding how extracted lactoferrin. Here, crystal structure...
Abstract Background Carbohydrate-active enzymes (CAZymes) form the most widespread and structurally diverse set of involved in breakdown, biosynthesis, or modification lignocellulose that can be found living organisms. However, structural diversity CAZymes has rendered targeted discovery novel extremely challenging, as these proteins catalyze many different chemical reactions are sourced by a vast array microbes. Consequently, uncharacterized members CAZyme families interest have been...
Abstract Respiratory syncytial virus (RSV) is the leading cause of infant hospitalization. All current available RSV therapeutics including antibody prophylaxis and adult vaccination target fusion glycoprotein (RSV-F).The seven neutralization sites on RSV-F are highlyconserved infrequently mutated. Here, we show that asingle amino acid mutation at position 305 in significantly alters antigenic recognition binding changes susceptibility to neutralizing antibodies. In an vitro evolution assay,...
Lactoferrin (Lf) is a bi-lobed, iron-binding protein found on mucosal surfaces and at sites of inflammation. Gram-negative pathogens from the Neisseriaceae Moraxellaceae families are capable using Lf as source iron for growth through process mediated by bacterial surface receptor that directly binds host Lf. This consists an integral outer membrane protein, lactoferrin binding A (LbpA), lipoprotein, B (LbpB). The N-lobe homologous transferrin B, TbpB, has been shown to facilitate in...