A5026864379- Metal-Catalyzed Oxygenation Mechanisms
- interferon and immune responses
- Metal complexes synthesis and properties
- Cancer Immunotherapy and Biomarkers
- CO2 Reduction Techniques and Catalysts
- Metalloenzymes and iron-sulfur proteins
- Virus-based gene therapy research
- Electron Spin Resonance Studies
- RNA modifications and cancer
- Crystallization and Solubility Studies
- Monoclonal and Polyclonal Antibodies Research
- X-ray Diffraction in Crystallography
- Plant Gene Expression Analysis
- Catalytic Alkyne Reactions
- Cancer Research and Treatments
- Photosynthetic Processes and Mechanisms
- Porphyrin and Phthalocyanine Chemistry
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Synthetic Organic Chemistry Methods
- Cyclopropane Reaction Mechanisms
- Parkinson's Disease Mechanisms and Treatments
- Cancer, Hypoxia, and Metabolism
- Adenosine and Purinergic Signaling
- RNA and protein synthesis mechanisms
- Global Health and Surgery
Merck & Co., Inc., Rahway, NJ, USA (United States)
2007-2022
Massachusetts Institute of Technology
2009-2015
Max Planck Institute for Biophysical Chemistry
2009
Rutgers, The State University of New Jersey
2005
University of California, San Diego
2005
Johns Hopkins University
2005
Pharmacological activation of the STING (stimulator interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report identification MSA-2, an orally available non-nucleotide human agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated stimulated interferon-β secretion in tumors, induced regression with durable antitumor immunity, synergized anti-PD-1 therapy. Experimental theoretical analyses showed...
Ribonucleotide reductases (RNRs) catalyze the conversionof nucleotides to 2′-deoxynucleotides and are classified on basis of metallo-cofactor used conduct this chemistry. The class Ia RNRs initiate nucleotide reduction when a stable diferric-tyrosyl radical (Y•, t1/2 4 days at °C) cofactor in β2 subunit transiently oxidizes cysteine thiyl (S•) active site α2 subunit. In α2β2 complex RNR from E. coli, researchers have proposed that hopping occurs reversibly over 35 Å along specific pathway...
Tyrosyl radicals (Y·s) are prevalent in biological catalysis and formed under physiological conditions by the coupled loss of both a proton an electron. Fluorotyrosines (FnYs, n = 1–4) promising tools for studying mechanism Y· formation reactivity, as their pKa values peak potentials span four units 300 mV, respectively, between pH 6 10. In this manuscript, we present directed evolution aminoacyl-tRNA synthetases (aaRSs) 2,3,5-trifluorotyrosine (2,3,5-F3Y) demonstrate ability to charge...
The gold(I)-catalyzed regioselective cyclizations of silyl ketene amides or carbamates with alkynes were utilized to construct cyclopentanes dehydro-delta-lactams.
Escherichia coli ribonucleotide reductase is an α2β2 complex and catalyzes the conversion of nucleoside 5′-diphosphates (NDPs) to 2′-deoxynucleotides (dNDPs). The reaction initiated by transient oxidation active-site cysteine (C439) in α2 a stable diferric tyrosyl radical (Y122•) cofactor β2. This occurs mechanism long-range proton-coupled electron transfer (PCET) over 35 Å through specific pathway residues: Y122•→ W48→ Y356 β2 Y731→ Y730→ C439 α2. To study details this process,...
Ribonucleotide reductase (RNR) catalyzes the conversion of nucleoside diphosphates to deoxynucleoside (dNDPs). The Escherichia coli class Ia RNR uses a mechanism radical propagation by which cysteine in active site large (α2) subunit is transiently oxidized stable tyrosyl (Y•) small (β2) over 35-Å pathway redox-active amino acids: Y122• ↔ [W48?] Y356 β2 Y731 Y730 C439 α2. When 3-aminotyrosine (NH2Y) incorporated place Y730, long-lived NH2Y730• generated α2 presence wild-type (wt)-β2,...
Ribonucleotide reductase (RNR) catalyzes conversion of nucleoside diphosphates (NDPs) to 2′-deoxynucleotides, a critical step in DNA replication and repair all organisms. Class-Ia RNRs, found aerobic bacteria eukaryotes, are complex two subunits: α2 β2. The β2 subunit contains an essential diferric–tyrosyl radical (Y122O•) cofactor that is needed initiate reduction NDPs the subunit. In this work, we investigated Y122O• mechanism Escherichia coli by hydroxyurea (HU), scavenger cancer...
Escherichia coli class Ia ribonucleotide reductase is composed of two subunits (α and β), which form an α2β2 complex that catalyzes the conversion nucleoside 5'-diphosphates to deoxynucleotides (dNDPs). β2 contains essential tyrosyl radical (Y122(•)) generates a thiyl (C439(•)) in α2 where dNDPs are made. This oxidation occurs over 35 Å through pathway amino acid intermediates (Y122 → [W48] Y356 Y731 Y730 C439 α2). However, chemistry preceded by slow protein conformational change(s) prevents...
Inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization novel series potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type ATP-competitive physicochemical properties were integrated with CNS drug-like through combination structure-based drug...
Escherichia coli class Ia ribonucleotide reductase (RNR) is composed of two subunits that form an active α2β2 complex. The nucleoside diphosphate substrates (NDP) are reduced in α2, 35 Å from the essential diferric-tyrosyl radical (Y122•) cofactor β2. Y122•-mediated oxidation C439 α2 occurs by a pathway (Y122 ⇆ [W48] Y356 β2 to Y731 Y730 α2) across α/β interface. absence structure precludes insight into location and at subunit proximity primary sequence conserved E350 suggested its...
E. coli ribonucleotide reductase (RNR) catalyzes the conversion of nucleotides to deoxynucleotides, a process that requires long-range radical transfer over 35 Å from tyrosyl (Y122•) within β2 subunit cysteine residue (C439) α2 subunit. The step is proposed occur by proton-coupled electron via specific pathway consisting Y122 → W48 Y356 in β2, across interface Y731 Y730 C439 α2. Using suppressor tRNA/aminoacyl-tRNA synthetase (RS) methodology, 3-aminotyrosine has been incorporated into...
Escherichia coli ribonucleotide reductase (RNR), an α2β2 complex, catalyzes the conversion of nucleoside 5′-diphosphate substrates (S) to 2′-deoxynucleoside 5′-diphosphates. α2 houses active site for nucleotide reduction and binding sites allosteric effectors (E). β2 contains essential diferric tyrosyl radical (Y122•) cofactor which, in presence S E, oxidizes C439 α a thiyl radical, C439•, initiate reduction. This oxidation occurs over 35 Å is proposed involve specific pathway: Y122• → W48...
The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe and evolution a picolinamide-derived lead series. Our initial optimization efforts aimed at improving potency CLK2 off-target selectivity compound 1 by modifying heteroaryl C-H hinge linker regions. This resulted in 12 which advanced deep into our operating plan (ROP) before aniline metabolite...
A thioglycoside aminotriol scaffold has been elaborated by acylation, reductive alkylation, sulfonation, phosphorylation, and other procedures to produce a library of 40 functionalized thioglycosides that superficially resemble the enzyme‐binding portions Mycobacterium tuberculosis detoxifier mycothiol its metabolic congeners. To extent these analogues mimic transition states derived from substrates mycothiol‐associated enzymes, they might prove useful as inhibitors and, ultimately, drug leads.
The zinc(II) complex (PATH)ZnOH, where PATH is an N2S(thiolate) ligand, has been investigated for its ability to promote the hydrolysis of phosphate triester tris(4-nitrophenyl) (TNP). TNP was examined as a function PATH-zinc(II) concentration, substrate and pH in water/ethanol mixture (66:33 v/v) at 25 degrees C. reaction first order both substrate, second-order rate constants were derived from linear plots observed pseudo-first-order versus zinc concentration different values. A pH-rate...
The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I IFN production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent antitumor activity. To exploit this mechanism, we synthesized a novel agonist, MSA-1, activates both mouse human with higher in vitro potency than cGAMP. Following intratumoral administration MSA-1 to panel syngeneic tumors...
Abstract The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I interferon production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent anti-tumor activity. To exploit this mechanism we synthesized a novel agonist, MSA-1, activates both mouse human with higher in vitro potency than cGAMP. MSA-1 was administered to immune-competent mice...
Considerable effort has been dedicated to the development of technology for site-specific incorporation unnatural amino acids into proteins, with nonsense codon suppression and expressed protein ligation emerging as two most promising methods. Recent research advances in which these methods have applied study function mechanism are briefly highlighted, potential efficient, widespread future use vitro vivo is critically evaluated.
The E. coli class Ia ribonucleotide reductase (RNR) catalyzes the de novo synthesis of deoxynucleoside 5ʹ‐diphosphates (dNDPs) using nucleoside (NDPs) as substrates. catalytic mechanism RNR requires an active site thiyl radical, which is generated via reversible oxidation by a tyrosyl radical cofactor located over 35 Å away. model for long range involves multiple proton‐coupled electron transfer (PCET) steps through aromatic amino acid residues. Efforts to study hopping have been challenging...
Escherichia coli class Ia ribonucleotide reductase (RNR) catalyzes the formation of all four deoxynucleoside 5′‐diphosphates from their corresponding nucleoside 5′‐diphosphates. Class RNRs are composed two homodimeric subunits, α2 and β2, that form active complex. A stable tyrosyl radical (Y 122 •) in β2 subunit generates a transient cysteine (C 439 located 35 Å away by mechanism is proposed to involve concerted movement protons electrons (proton‐coupled electron transfer or PCET) through...