A5017622906- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- Integrated Circuits and Semiconductor Failure Analysis
- Cystic Fibrosis Research Advances
- Neonatal Respiratory Health Research
- CRISPR and Genetic Engineering
- Inhalation and Respiratory Drug Delivery
- Crystallization and Solubility Studies
- Poxvirus research and outbreaks
- interferon and immune responses
- Drug Transport and Resistance Mechanisms
- X-ray Diffraction in Crystallography
- Adenosine and Purinergic Signaling
- Toxin Mechanisms and Immunotoxins
- HIV/AIDS drug development and treatment
- Helicobacter pylori-related gastroenterology studies
- Electrostatic Discharge in Electronics
- Herpesvirus Infections and Treatments
- Advanced Glycation End Products research
- Clostridium difficile and Clostridium perfringens research
St. John's University
2017-2024
DNA death grip Poly(ADP-ribose) polymerase–1 (PARP-1) binds to breaks and recruits repair components. Cancer-killing PARP-1 inhibitor (PARPi) compounds all block the same catalytic site but exhibit vastly different efficacy. Zandarashvili et al. investigated molecular impact of PARPi binding (see Perspective by Slade Eustermann). Different molecules perturb allostery in diverse manners: Some drive promote release from DNA, others retention. These insights help explain efficacies clinic...
Poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity PARP proteins. Optimization our lead compound 1 ((Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC50 = 434 nM) led to tetrazolyl analogue (51, 35 with improved inhibition. Isosteric replacement tetrazole ring carboxyl group (60, 68 gave promising new lead, which was subsequently optimized obtain analogues potent values (4–197 nM). enzyme...
Catalytic poly(ADP-ribose) production by PARP1 is allosterically activated through interaction with DNA breaks, and PARP inhibitor compounds have the potential to influence allostery in addition preventing catalytic activity. Using benzimidazole-4-carboxamide pharmacophore present first generation veliparib, a series of 11 derivatives was designed, synthesized, evaluated as allosteric inhibitors, premise that bulky substituents would engage regulatory helical domain (HD) thereby promote...
Clostridium difficile infection (CDI) is the leading cause of healthcare-associated in United States. Therefore, development novel treatments for CDI a high priority. Toward this goal, we began vitro screening structurally diverse in-house library 67 compounds against two pathogenic C. strains (ATCC BAA 1870 and ATCC 43255), which yielded hit compound, 2-methyl-8-nitroquinazolin-4(3H)-one (2) with moderate potency (MIC = 312/156 μM). Optimization 2 gave lead compound 6a...
A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective understanding the structural requirements ligands binding to a highly perplexing substrate-binding site P-glycoprotein (P-gp) their effect modulating ATPase function efflux pump. Compound 1, stimulator P-gp activity, transformed inhibitory compounds 39, 53, 109. The inhibition by these predominantly contributed presence cyclohexyl group in lieu 2-aminobenzophenone moiety 1....
Abstract Background High mobility group box 1 protein (HMGB1) is an alarmin following its release by immune cells upon cellular activation or stress. levels of extracellular HMGB1 play a critical role in impairing the clearance invading pulmonary pathogens and dying neutrophils injured lungs cystic fibrosis (CF) acute respiratory distress syndrome (ARDS). A heparin derivative, 2-O, 3-O desulfated (ODSH), has been shown to inhibit from macrophage cell line efficacious increasing bacterial...