A5045660231- COVID-19 Clinical Research Studies
- Cancer, Hypoxia, and Metabolism
- SARS-CoV-2 and COVID-19 Research
- Epigenetics and DNA Methylation
- ATP Synthase and ATPases Research
- RNA modifications and cancer
- Adenosine and Purinergic Signaling
- Long-Term Effects of COVID-19
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Advanced NMR Techniques and Applications
- Pneumocystis jirovecii pneumonia detection and treatment
- Neonatal Health and Biochemistry
- Glioma Diagnosis and Treatment
- S100 Proteins and Annexins
- Advanced MRI Techniques and Applications
- Mitochondrial Function and Pathology
- Erythrocyte Function and Pathophysiology
- Nanoplatforms for cancer theranostics
- Pharmacological Receptor Mechanisms and Effects
- Cancer-related gene regulation
- Virus-based gene therapy research
- Heme Oxygenase-1 and Carbon Monoxide
- Hepatitis C virus research
- Legionella and Acanthamoeba research
The University of Texas MD Anderson Cancer Center
2018-2024
The University of Texas Southwestern Medical Center
2024
The University of Texas Health Science Center at Houston
2021-2023
While remdesivir has garnered much hope for its moderate anti-Covid-19 effects, parent nucleoside, GS-441524, been overlooked. Pharmacokinetic analysis of evidences premature serum hydrolysis to GS-441524; GS-441524 is the predominant metabolite reaching lungs. With synthetic simplicity and
Feline infectious peritonitis (FIP) is a fatal disease of cats that currently lacks licensed and affordable vaccines or antiviral therapeutics. The has spectrum clinical presentations including an effusive (“wet”) form non-effusive (“dry”) form, both which may be complicated by neurologic ocular involvement. feline coronavirus (FCoV) biotype, termed virus (FIPV), the etiologic agent FIP. objective this study was to determine compare in vitro efficacies viral protease inhibitors GC376...
Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. MTAP-deleted cell lines culture show elevation MTAP's substrate metabolite, (MTA). High levels MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated vitro, the clinical relevance relies on exhibiting...
Remdesivir is a nucleoside monophosphoramidate prodrug that has been FDA approved for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of remdesivir COVID-19 remains contentious, as several trials have not found statistically significant differences in either time to improvement or mortality between remdesivir-treated and control groups.
Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and mortality rate remains >95% in US. Glycolysis is very important infectious trophozoite lifecycle stage inhibitors of glucose metabolism have been found be toxic pathogen. Recently, human enolase 2 (ENO2) phosphonate developed as agents treat glioblastoma...
Quantitative imaging of apoptosis in vivo could enable real-time monitoring acute cell death pathologies such as traumatic brain injury, well the efficacy and safety cancer therapy. Here, we describe development validation F-18-labeled caspase-3 substrates for PET/CT apoptosis. Preliminary studies identified O-benzylthreonine-containing substrate 2MP-TbD-AFC a highly caspase 3-selective cell-permeable fluorescent reporter. This lead compound was converted into radiotracer [18F]-TBD, which...
Despite being FDA-approved for COVID-19, the clinical efficacy of remdesivir (Veklury®) remains contentious. We previously pointed out pharmacokinetic, pharmacodynamic and toxicology reasons why its parent nucleoside GS-441524, is better suited COVID-19 treatment. Here, we assess oral bioavailability GS-441524 in beagle dogs show that plasma concentrations ~24-fold higher than EC50 against SARS-CoV-2 are easily safely sustained. These data support translation as an agent COVID-19.
Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption generally tolerated in mammals. Unfortunately, anemia known dose-limiting side effect these inhibitors presents major caveat to development antiglycolytic therapies. We developed specific enolase –...
ABSTRACT Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and mortality rate remains >95% in US. Glycolysis is very important infectious trophozoite lifecycle stage inhibitors of glucose metabolism have been found be toxic pathogen. Recently, human enolase 2 (ENO2) phosphonate developed as agents treat...
Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition paralogous isoform, 2 (ENO2). A previous work described sustained tumor regression activities a substrate-competitive phosphonate inhibitor ENO2, 1-hydroxy-2-oxopiperidin-3-yl (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model glioblastoma [Nature Metabolism 2020, 2, 1423–1426]. Due poor pharmacokinetics...
We recently reported that SF2312 ((1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid), a phosphonate antibiotic with previously unknown mode of action, is potent inhibitor the glycolytic enzyme, Enolase. can only be synthesized as racemic-diastereomeric mixture. However, co-crystal structures Enolase 2 (ENO2) have consistently shown (3S,5S)-enantiomer binds to active site. The acidity alpha proton at C-3, which deprotonates under mildly alkaline conditions, results in racemization; thus...
With the rising prevalence of multidrug resistance, there is an urgent need to develop novel antibiotics. Many putative antibiotics demonstrate promising in vitro potency but fail vivo due poor drug-like qualities (e.g., serum half-life, oral absorption, solubility, and toxicity). These properties can be modified through addition chemical protecting groups, creating "prodrugs" that are activated prior target inhibition. Lipophilic prodrugging techniques, including attachment a...
The phosphonate group is a key pharmacophore in many antiviral, antimicrobial, and antineoplastic drugs. Due to its high polarity short retention time, detecting quantifying such phosphonate-containing drugs with LC/MS-based methods are challenging require derivatization hazardous reagents. Given the emerging importance of drugs, developing practical, accessible, safe method for their quantitation pharmacokinetics (PK) studies desirable. NMR-based often employed drug discovery but seldom...
ABSTRACT Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We recently demonstrated that SF2312, a natural product phosphonate antibiotic, is potent inhibitor glycolytic enzyme Enolase with potential utility collateral lethality-based Enolase-deficient glioblastoma (GBM). However, phosphonates are anionic at physiological pH, limiting cell and tissue permeability. Here, we show addition pivaloyloxymethyl (POM) groups to SF2312 (POMSF) dramatically increases...
Ongoing compilation of data supporting clinical advancement GS-441524, the parent nucleoside remdesivir, for treatment Covid-19. Version 3. Last updated: Aug. 29, 2020.
Metabolically labile prodrugs can experience stark differences in catabolism incurred by the chosen route of administration. This is especially true for phosph(on)ate prodrugs, which successive promoiety removal transforms a lipophilic molecule into increasingly polar compounds. We previously described phosphonate inhibitor enolase (HEX) and its bis-pivaloyloxymethyl ester prodrug (POMHEX) capable eliciting strong tumor regression murine model 1 (ENO1)-deleted glioblastoma following...
Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of Enolase for cancers harboring deletions ENO1. Here, we describe the application nitroheterocycle pro-drugs capitalizing on tumor hypoxia. These bioreducible exhibit up to 14-fold greater potency under hypoxic conditions compared normoxia and robust stability biological fluids. Our work provides strong proof-of-concept using bioreduction as pro-drug delivery strategy...