A5091579621- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Hepatitis C virus research
- Sulfur Compounds in Biology
- Cytomegalovirus and herpesvirus research
- Cancer therapeutics and mechanisms
- Drug-Induced Hepatotoxicity and Protection
- Biochemical and Molecular Research
- Cannabis and Cannabinoid Research
- Antibiotics Pharmacokinetics and Efficacy
- Endoplasmic Reticulum Stress and Disease
- Calcium signaling and nucleotide metabolism
- Alzheimer's disease research and treatments
- Calpain Protease Function and Regulation
- Redox biology and oxidative stress
- Alkaloids: synthesis and pharmacology
- Alcohol Consumption and Health Effects
- Sirtuins and Resveratrol in Medicine
- Hepatitis B Virus Studies
- Neuropeptides and Animal Physiology
- Mosquito-borne diseases and control
- Autophagy in Disease and Therapy
- Nanoplatforms for cancer theranostics
- Herpesvirus Infections and Treatments
- Pain Mechanisms and Treatments
University of Minnesota System
2024
University of Minnesota
2015-2024
South Dakota State University
2011-2014
Shanghai Institute of Pharmaceutical Industry
2008
Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19. However, RDV can be given by intravenous route, there a pressing medical need oral antivirals. Significant evidence suggests that role of parent nucleoside GS-441524 in clinical outcomes could largely underestimated. We performed an vitro vivo metabolism pharmacokinetics (DMPK) assessment to examine potential RDV, particularly GS-441524, as drugs. In our assessments, exhibited...
Taking advantage of the uniquely constricted active site SARS-CoV-2 Nsp14 methyltransferase, we have designed bisubstrate inhibitors interacting with SAM and RNA substrate binding pockets. Our efforts led to nanomolar including compounds 3 10. As a prototypic inhibitor, compound also has an excellent selectivity profile over panel human methyltransferases. Remarkably, C-nucleoside 10 exhibits high antiviral activity low cytotoxicity, leading therapeutic index (CC50/EC50) greater than 139....
Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On basis our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized new integrase strand transfer (INST) inhibitor type featuring 5-N-benzylcarboxamide moiety. Significantly, 6-alkylamino variant this chemotype consistently conferred low nanomolar inhibitory activity...
Increased oxidative stress and inflammation are implicated in the pathogenesis of Alzheimer's disease. Treatment with hydrogen sulfide (H2S) H2S donors such as sodium hydrosulfide (NaSH) can reduce preclinical studies, however clinical benefits treatments rather ambiguous. This is partly due to poor stability bioavailability donors, requiring impractically large doses that associated dose-limiting toxicity. Herein, we identified a bioavailable 3-mercaptopyruvate prodrug, sulfanegen, which...
Derived from our previously reported human sirtuin 2 (SIRT2) inhibitors that were based on a 5-aminonaphthalen-1-yloxy nicotinamide core structure, 5-((3-amidobenzyl)oxy)nicotinamides offered excellent activity against SIRT2 and high isozyme selectivity over SIRT1 SIRT3. Selected compounds also exhibited generally favorable in vitro absorption, distribution, metabolism, excretion properties. Kinetic studies revealed representative inhibitor acted competitively both NAD(+) the peptide...
Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability confer antiviral phenotypes in both early and late phases of viral replication. However, prohibitively low metabolic stability renders a poor lead. We report herein our medicinal chemistry efforts toward identifying novel metabolically stable binding site. Specifically, we replaced inter-domain-interacting, electron-rich...
HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents appealing antiviral target. Several CA-targeting small molecules various chemotypes have been studied, but the peptidomimetic PF74 has drawn particular interest due to its potent activity, well-characterized binding mode, unique mechanism action. Importantly, competes against host factors for binding, conferring highly desirable phenotypes. However, further development is hindered by...
Hepatitis B virus (HBV) capsid assembly modulators (CpAMs) have shown promise as potent anti-HBV agents in both preclinical and clinical studies. Herein, we report our efforts identifying novel CpAM hits via a structure-based virtual screening against small molecule protein-protein interaction (PPI) library, pharmacophore-guided compound design synthesis. Curated compounds were first assessed thermal shift assay (TSA), the TSA further evaluated an antiviral assay. These led to discovery of...
Inhibitors of human p97 (also known as valosin-containing protein) have been actively pursued because their potential therapeutic applications in cancer and other diseases. However, covalent irreversible inhibitors not well explored. Herein, we report our design, synthesis, biological evaluation p97. Among an amide a reverse series synthesized, identified inhibitor whose functional irreversibility has established both vitro cells. Also importantly, mass spectrometry reveals three cysteine...
Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage tyrosyl phosphodiesterase 2 (TDP2) could render cancer cells resistant poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes the deazaflavin inhibitor core. By introducing additional phenyl...
HIV-1 replication kinetics inherently depends on the availability of cellular dNTPs for viral DNA synthesis. In activated CD4+ T cells and other rapidly dividing cells, concentrations are high reverse transcription occurs in an efficient manner. contrast, nondividing such as macrophages have lower dNTP pools, which restricts transcription. Clofarabine is FDA approved ribonucleotide reductase inhibitor, has shown potent antiretroviral activity transformed cell lines. Here, we explore potency,...
Cancer metastasis is the major cause of cancer mortality. Despite extensive research efforts, effective treatment for still lacking. involves 4 essential steps: cell detachment, migration, invasion, and adhesion. Detachment first required step metastasis. Glutathione disulfide (GSSG) derived from oxidation glutathione (GSH), which present in biological systems millimolar concentration. Although GSSG commercially available, impact on functions/dysfunctions has not been fully explored due to...
Endoplasmic reticulum (ER) stress has been shown to be involved in the hepatotoxicity of acetaminophen (APAP). Guanabenz (GA), a widely known antihypertensive drug, is reported exhibit an anti-ER effect. In this study, we investigated potential GA as antidote against APAP-induced hepatotoxicity. The underlying biochemical mechanisms for hepatoprotective effect were explored. Here found that treatment mice with (10 mg/kg) before APAP overdose dramatically prevented liver enzyme elevation and...
5-Azacytidine (5-aza-C) is a ribonucleoside analog that induces the lethal mutagenesis of human immunodeficiency virus type 1 (HIV-1) by causing predominantly G-to-C transversions during reverse transcription. 5-Aza-C could potentially act primarily as ribonucleotide (5-aza-CTP) or deoxyribonucleotide (5-aza-2'-deoxycytidine triphosphate [5-aza-dCTP]) In order to determine primary form 5-aza-C active against HIV-1, Illumina sequencing was performed using proviral DNA from cells treated with...
Guided by antiproliferative activity in MIA PaCa-2 cells, we have performed preliminary structure–activity relationship studies on N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides. Two selected compounds showed submicromolar and good metabolic stability. Both reduced mTORC1 increased autophagy at the basal level. In addition, they disrupted autophagic flux interfering with reactivation clearance of LC3-II under starvation/refeed conditions, as evidenced accumulation abnormal LC3 labeled...