R-3 Repository :: Browsing by Author "Ball, Zachary T."

Browsing by Author "Ball, Zachary T."

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A photochemical C=C cleavage process: toward access to backbone N-formyl peptides
(Beilstein-Institut, 2021) Wang, Haopei; Ball, Zachary T.
Photo-responsive modifications and photo-uncaging concepts are useful for spatiotemporal control of peptides structure and function. While side chain photo-responsive modifications are relatively common, access to photo-responsive modifications of backbone N–H bonds is quite limited. This letter describes a new photocleavage pathway, affording N-formyl amides from vinylogous nitroaryl precursors under physiologically relevant conditions via a formal oxidative C=C cleavage. The N-formyl amide products have unique properties and reactivity, but are difficult or impossible to access by traditional synthetic approaches.
ADAM8 signaling drives neutrophil migration and ARDS severity
(American Society for Clinical Investigation, 2022) Conrad, Catharina; Yildiz, Daniela; Cleary, Simon J.; Margraf, Andreas; Cook, Lena; Schlomann, Uwe; Panaretou, Barry; Bowser, Jessica L.; Karmouty-Quintana, Harry; Li, Jiwen; Berg, Nathaniel K.; Martin, Samuel C.; Aljohmani, Ahmad; Moussavi-Harami, S. Farshid; Wang, Kristin M.; Tian, Jennifer J.; Magnen, Mélia; Valet, Colin; Qiu, Longhui; Singer, Jonathan P.; Eltzschig, Holger K.; Bertrams, Wilhelm; Herold, Susanne; Suttorp, Norbert; Schmeck, Bernd; Ball, Zachary T.; Zarbock, Alexander; Looney, Mark R.; Bartsch, Jörg W.
Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.
Catalytic Organosilane Activation with Copper Complexes
(2013-07-24) Herron, Jessica; Ball, Zachary T.; Tour, James M.; Verduzco, Rafael
The development of reactive organometallics has become a vital part synthetic chemistry. Organosilanes potentially represent a cheap, robust, and environmentally benign precursor to reactive organometallics, but the nature of the very stable C−Si bond has generally prevented their use as precursors to more reactive organometallics. We present investigations into copper fluoride complexes which activate organosilanes in anhydrous media under mild conditions, effecting transmetalation to produce stable and in some cases isolable organocopper species containing sensitive functional groups including carbonyl groups, aryl bromides, benzylic chlorides, and alkyl ketones. This discovery allows us to better understand the fundamental reactivity of presumed intermediates in copper-catalyzed reactions and to develop new catalytic bond-forming processes including allylations of aldehydes, 1,4-addition of vinyl epoxides, and intramolecular ring closures.
Convenient analysis of protein modification by chemical blotting with fluorogenic “click” reagents
(Royal Society of Chemistry, 2015) Ohata, Jun; Farrukh, Vohidov; Ball, Zachary T.
Direct visualization of bioorthogonal alkyne or azide handles using fluorogenic azide–alkyne cycloaddition conducted on the surface of a blot membrane. The method eliminates the need for separation steps to remove excess small molecule reagents before attachment of antigen molecules or other visualization handles, and is especially useful for the analysis of peptides and small proteins. A variety of potential fluorogenic reagents are assessed, and sensitivity (<0.1 picomole) similar to current commercially available fluorescence imaging methods is possible.
Copper-mediated peptide arylation selective for the N-terminus
(Royal Society of Chemistry, 2020) Miller, Mary K.; Wang, Haopei; Hanaya, Kengo; Zhang, Olivia; Berlaga, Alex; Ball, Zachary T.
Polypeptides present remarkable selectivity challenges for chemical methods. Amino groups are ubiquitous in polypeptide structure, yet few paradigms exist for reactivity and selectivity in arylation of amine groups. This communication describes the utilization of boronic acid reagents bearing certain o-electron withdrawing groups for copper-mediated amine arylation of the N-terminus under mild conditions and primarily aqueous solvent. The method adds to the toolkit of boronic acid reagents for polypeptide modification under mild conditions in water that shows complete selectivity for the N-terminus in the presence of lysine side chains.
Developing Dirhodium-Complexes for Protein Inhibition and Modification & Copper-Catalyzed Remote Chlorination of Alkyl-Hydroperoxides
(2013-09-16) Kundu, Rituparna; Ball, Zachary T.; Marti, Angel A.; Biswal, Sibani Lisa
The work describes the development of a new class of protein-inhibitors for protein-protein interactions, based on metallopeptides comprised of a dirhodium metal center. The metal incorporation in the peptide sequence leads to high increase in binding affinity of the inhibitors. The source of this strong affinity is the interaction of histidine on the protein surface with the rhodium center. In addition to this work, rhodium-based small molecule inhibitors for FK-506 binding proteins are investigated. Also, methodology for rhodium-catalyzed modification of proteins containing surface cysteine has been developed where a simple rhodium(II) complex catalyzes cysteine modification with diazo reagents. The reaction is marked by clean cysteine selectivity and mild reaction conditions. The resulting linkage is significantly more stable in human plasma serum, when compared to common maleimide reagents. Apart from this body of work in chemical-biology, the thesis contains the discussion of development of copper-catalyzed remote chlorination of alkyl hydroperoxides. The atom transfer chlorination utilizes simple ammonium chloride salts as the chlorine source and the internal redox process requires no external redox reagents.
Direct formation and site-selective elaboration of methionine sulfoximine in polypeptides
(Royal Society of Chemistry, 2022) Ding, Yuxuan; Pedersen, Simon S.; Lin, Alex; Qian, Ruoyu; Ball, Zachary T.
Sulfoximines are emerging moieties for medicinal and biological chemistry, due in part to their efficacy in selective inhibition of amide-forming enzymes such as γ-glutamylcysteine synthetase. While small-molecule sulfoximines such as methionine sulfoximine (MSO) and its derivatives are well studied, structures with methionine sulfoximine residues within complex polypeptides have been generally inaccessible. This paper describes a straightforward means of late-stage one-step oxidation of methionine residues within polypeptides to afford NH-sulfoximines. We also present chemoselective subsequent elaboration, most notably by copper(II)-mediated N–H cross-coupling at methionine sulfoximine residues with arylboronic acid reagents. This development serves as a strategy to incorporate diverse sulfoximine structures within natural polypeptides, and also identifies the methionine sulfoximine residue as a new site for bioorthogonal, chemoselective bioconjugation.
Hybrid organic-inorganic inhibitors of a PDZ-peptide interaction that regulates CFTR endocytic fate
(Wiley-VCH Verlag, 2012) Kundu, Rituparna; Cushing, Patrick R.; Popp, Brian V.; Zhao, Yu; Madden, Dean R.; Ball, Zachary T.
Luminogenic iridium azide complexes
(Royal Society of Chemistry, 2015) Ohata, Jun; Vohidov, Farrukh; Aliyan, Amirhossein; Huang, Kewei; Martí, Angel A.; Ball, Zachary T.
The synthesis and characterization of luminogenic, bioorthogonal iridium probes is described. These probes exhibit long photoluminescence lifetimes amenable to time-resolved applications. A simple, modular synthesis via 5-azidophenanthroline allows structural variation and allows optimization of cell labeling.
Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors
(Royal Society of Chemistry, 2015) Vohidov, Farrukh; Knudsen, Sarah E.; Leonard, Paul G.; Ohata, Jun; Wheadon, Michael J.; Popp, Brian V.; Ladbury, John E.; Ball, Zachary T.
Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(II) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(II) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC50 200 nM).
Rh(II) metallopeptides for asymmetric catalysis
(2015-02-17) Sambasivan, Ramya; Ball, Zachary T.; Engel, Paul S.; Verduzco, Rafael
The development of peptides as chiral ligands for asymmetric Rh(II) catalysis is discussed in this work. Mother Nature’s solution to chiral ligand design is to make use of the naturally available chiral building blocks – amino acids. Polypeptides, built from amino acids, provide a diverse, modular and functional-group-rich framework for the development of selective transition- metal catalysts and enable facile ligand screening. The dirhodium core has a paddlewheel structure that can ligate readily to the side chain carboxylate of aspartate or glutamate in a peptide chain. When a peptide containing aspartates or glutamates in the i and i+4 position is complexed to dirhodium, the transition metal complex thus formed has a defined peptide secondary structure with retention of catalytic activity at the metal center. The first-generation approach used a solution-phase library of dirhodium bis-peptide catalysts for the enantioselective Si–H bond insertion and cyclopropanation. The parallel and anti-parallel orientation of bis-peptide catalysts was determined by pyrene fluorescence. Subsequently, parallel on-bead screening of catalyst libraries allowed significantly higher throughput by obviating the need for purification and isolation of individual catalysts. This enables the synthesis and screening of catalysts in 96-well plate format within a few days. More recently, a mono-peptide catalyst with a tridentate eq-eq-ax peptide ligand has been identified which exhibits differential behavior in solution and on bead. New insights into the development of immobilized homogeneous catalysts for stereoselective catalysis are discussed.
Rhodium(II) Proximity-Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti-Leukemia Activity
(Wiley, 2015) Minus, Matthew B.; Liu, Wei; Vohidov, Farrukh; Kasembeli, Moses M.; Long, Xin; Krueger, Michael; Stevens, Alexandra; Kolosov, Mikhail I.; Tweardy, David J.; Sison, Edward Allen R.; Redell, Michele S.; Ball, Zachary T.
Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML.
Sensing amyloid aggregation using photoluminescent ruthenium(II) probes
(2014-04-24) Cook, Nathan Patrick; Marti, Angel A.; Ball, Zachary T.; Segatori, Laura
Amyloid proteins are a broad class of proteins that are implicated in a wide number of diseases. This thesis explores the use of photoluminescent ruthenium(II) complexes for the detection of amyloid aggregation. Furthermore, we report the detection of amyloid aggregates from test tube to cell culture using photoluminescent and lifetime measurements.
Small molecule conjugates with dimetal species for protein inhibition
(2015-06-02) Ball, Zachary T.; Kundu, Rituparna; Popp, Brian V.; Madden, Dean R.; Cushing, Patrick R.; Rice University; Trustees of Dartmouth College; United States Patent and Trademark Office
Methods for targeting a protein by providing an inhibitor covalently linked to a rhodium(II) complex, introducing the inhibitor to the target protein and allowing the inhibitor and protein to interact. The rhodium(II) complex covalently linked to the inhibitor binds the target protein both inorganically and organically and forms stabilizing secondary contacts between the rhodium(II) complex and the protein.
Studies of Cu-catalyzed installation and photochemical removal of peptide N-H modifications
(2021-09-17) Wang, Haopei; Ball, Zachary T.
Methods for selective modification of peptides are important for chemical biology and pharmaceutical industries. Among many reagents for modification, boronic acids have become a popular reaction partner for peptide under mild conditions. On the other hand, nitro aryl compounds have various roles in nature and industries. Its photosensitive properties lead to various photoreactions and applications as photo-labile protecting groups. This thesis has two main components: one component is about modification of peptides using boronic acids, and the other about the fate of nitro aryl moiety installed onto peptide using boronic acids. Chapter 1,4, and 5 belong to the first component. Chapter 1 is a review of peptide modification using boronic acids to form new C-C bond. Chapter 4 presents the development of a new method for peptide N-terminal modification using certain o-substituted boronic acids and copper (II) salts. The focus will be on method development for determining yield, and boronic acids scope screening. Chapter 5 will present an attempt of synthesizing peptide thioesters using histidine-directed peptide backbone arylation. Preliminary data with model peptides and potential future direction of the project will be discussed. Chapter 2 and 3 focus on nitro aryl compounds. Chapter 2 is a review about various photoreactions of nitro aryl compounds. Chapter 3 is a study of byproducts from photocleavage of nitroaromatic-containing peptide modification using small-molecule models. A bifurcating mechanism is proposed for reactions at different pH.
Synthesis and Applications of Dirhodium Metallopeptides
(2012-09-05) Zaykov, Alexander; Ball, Zachary T.; Parry, Ronald J.; Silberg, Jonathan J.
The work describes the development of a new class of synthetic metallopeptides that features a dirhodium metal center. Combination of peptide and dirhodium properties leads to unique effects on peptide structure, peptide-protein interactions, and metal catalytic activity aimed at small molecule as well as protein substrates. Dirhodium is directly bound to carboxylate side chains of aspartate or glutamate yielding kinetically inert coordination complexes. This improves stability, allows purification and provides enhanced biocompatibility. Bridging of two side chains in the same sequence enables control of the peptide secondary structure. Dirhodium metallopeptides are applied to regulate coiled coil dimerization, stabilize and induce helical secondary structure, catalyze enantioselective organometallic transformation, and serve as ligands for proteins. These results lead to the development of hybrid organic-inorganic therapeutic agents, biological probes for study of protein-protein interactions, and enantioselective metallopeptide catalysis.

Browsing by Author "Ball, Zachary T."

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