A5071427554- Computational Drug Discovery Methods
- Ubiquitin and proteasome pathways
- Protein Structure and Dynamics
- DNA Repair Mechanisms
- Antibiotic Resistance in Bacteria
- Cancer therapeutics and mechanisms
- Antimicrobial Resistance in Staphylococcus
- Microbial Natural Products and Biosynthesis
- HIV/AIDS drug development and treatment
- Cancer-related Molecular Pathways
- RNA Research and Splicing
- Biochemical and Molecular Research
- Pharmacogenetics and Drug Metabolism
- Synthesis and bioactivity of alkaloids
- Synthesis and Characterization of Heterocyclic Compounds
- Cytomegalovirus and herpesvirus research
- Enzyme Structure and Function
- Marine Sponges and Natural Products
- Synthesis and Biological Evaluation
- Drug Transport and Resistance Mechanisms
- Synthesis and Characterization of Pyrroles
- Microtubule and mitosis dynamics
- Synthesis of heterocyclic compounds
- Antimicrobial Peptides and Activities
- HIV Research and Treatment
United States Military Academy
2016-2025
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010-2024
Scripps Research Institute
1998-2002
University of Virginia
1998-2001
McCormick (United States)
2001
Villanova University
1994
Concise, efficient total syntheses of ningalin A (1), lamellarin O (2), lukianol (3), and permethyl storniamide (5) are detailed on the basis a common heterocyclic azadiene Diels−Alder strategy (1,2,4,5-tetrazine → 1,2-diazine pyrrole) ideally suited for construction densely functionalized pyrrole cores found in three classes marine natural products. Examination products number synthetic intermediates revealed that some including (2) (3) exhibit modest cytotoxic activity against both...
Abstract Checkpoint kinase 1 (CHK1) is an essential serine/threonine that responds to DNA damage and stalled replication. CHK1 for maintenance of replication fork viability during exposure antimetabolites. In human tumor cell lines, ablation function antimetabolite led accumulation double-strand breaks death. Here, we extend these observations confirm CHK2 does not contribute phenotypes may diminish them. Furthermore, concomitant suppression cyclin-dependent (CDK) activity sufficient...
New inhibitors of wall teichoic acid biosynthesis restore susceptibility drug-resistant staphylococci to β-lactam antibiotics.
The nature and the size of benzylic substituent are shown to be key controlling receptor selectivity (CCR5 vs M1, M2) potency in title compounds. Optimization lead methyl compound 3 led methoxymethyl analogue 30, which had excellent oral bioavailability rats monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor HIV-1 entry into target cells, is currently clinical trials.
Modern medicine is founded on the discovery of penicillin and subsequent small molecules that inhibit bacterial peptidoglycan (PG) cell wall synthesis. However, new chemically mechanistically distinct classes PG inhibitors has become exceedingly rare, prompting speculation intracellular enzymes involved in precursor synthesis are not 'druggable' targets. Here, we describe a β-lactam potentiation screen to identify augment activity β-lactams against methicillin-resistant Staphylococcus aureus...
Here we describe a chemical biology strategy performed in Staphylococcus aureus and epidermidis to identify MnaA, 2-epimerase that demonstrate interconverts UDP-GlcNAc UDP-ManNAc modulate substrate levels of TarO TarA wall teichoic acid (WTA) biosynthesis enzymes. Genetic inactivation mnaA results complete loss WTA dramatic vitro β-lactam hypersensitivity methicillin-resistant S. (MRSA) (MRSE). Likewise, the antibiotic imipenem exhibits restored bactericidal activity against mutants...
Acinetobacter baumannii is a Gram-negative pathogen responsible for pneumonia and wound, bloodstream, urinary tract infections, particularly patients in intensive care units. Using phenotypic screening we have identified novel class of small molecule inhibitors that potent highly selective antibacterial activity against baumannii. Resistance selection the molecular target as MsbA, an essential ABC transporter functions by flipping lipid A across inner membrane most gram-negative bacteria....
To combat the threat of antibiotic-resistant Gram-negative bacteria, novel agents that circumvent established resistance mechanisms are urgently needed. Our approach was to focus first on identifying bioactive small molecules followed by chemical lead prioritization and target identification. Within this annotated library bioactives, we identified a molecule with activity against efflux-deficient Escherichia coli other sensitized Gram-negatives. Further studies suggested compound inhibited...
Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat constitutes growing threat human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms essential addressing this critical medical need. Herein, we describe our efforts inhibit the A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC)...
We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor TarO, early stage enzyme in biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 125 nM assay possessed very high lipophilicity (clogP = 7.1) with no measurable solubility PBS buffer. Structure-activity relationship (SAR) studies resulted series compounds improved lipophilic ligand efficiency (LLE) consistent reduction...
Nonessential enzymes in the staphylococcal wall teichoic acid (WTA) pathway serve as highly validated β-lactam potentiation targets. MnaA (UDP-GlcNAc 2-epimerase) plays an important role early step of WTA biosynthesis by providing activated form ManNAc. Identification a selective inhibitor would provide tool to interrogate contribution enzyme well adjuvant restore activity against methicillin-resistant Staphylococcus aureus (MRSA). However, development epimerase functional assay can be...