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Synthesis And Evaluation Of Anti-Hiv Activity Of Mono- And Di-Substituted Phosphonamidate Conjugates Of Tenofovir, Aaminat Qureshi, Louise A. Ouattara, Naglaa Salem El-Sayed, Amita Verma, Gustavo F. Doncel, Muhammad Iqbal Choudhary, Hina Siddiqui, Keykavous Parang 2022 University of Karachi

Synthesis And Evaluation Of Anti-Hiv Activity Of Mono- And Di-Substituted Phosphonamidate Conjugates Of Tenofovir, Aaminat Qureshi, Louise A. Ouattara, Naglaa Salem El-Sayed, Amita Verma, Gustavo F. Doncel, Muhammad Iqbal Choudhary, Hina Siddiqui, Keykavous Parang

Pharmacy Faculty Articles and Research

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several classes of ...


Defining The Substrate Envelope Of Sars-Cov-2 Main Protease To Predict And Avoid Drug Resistance, Ala M. Shaqra, Sarah N. Zvornicanin, Qiu Yu J. Huang, Gordon J. Lockbaum, Mark Knapp, Laura Tandeske, David T. Bakan, Julia M. Flynn, Daniel N. Bolon, Stephanie Moquin, Dustin Dovala, Nese Kurt Yilmaz, Celia A. Schiffer 2022 UMass Chan Medical School

Defining The Substrate Envelope Of Sars-Cov-2 Main Protease To Predict And Avoid Drug Resistance, Ala M. Shaqra, Sarah N. Zvornicanin, Qiu Yu J. Huang, Gordon J. Lockbaum, Mark Knapp, Laura Tandeske, David T. Bakan, Julia M. Flynn, Daniel N. Bolon, Stephanie Moquin, Dustin Dovala, Nese Kurt Yilmaz, Celia A. Schiffer

Schiffer Lab Publications

Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (M(pro)) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution ...


Biowill - Characterising Willow Bark Bio-Actives For Skin Therapies, Arnold Marisa 2022 Department of Biological and Pharmaceutical Sciences, Munster Technological University, Kerry, Ireland

Biowill - Characterising Willow Bark Bio-Actives For Skin Therapies, Arnold Marisa

ORBioM (Open Research BioSciences Meeting)

Willow bark is considered as a disposable by-product when processing willow for biomass. Willow (Salix) is known to contain high value bioactive compounds which include salicin and its derivatives, and other phytochemicals of interest such as polyphenols and flavonoids. The plant is historically known as the primary source of salicylates to which the well-known drug aspirin is derived from. The work forms part of the Interreg project BioWILL, which is focused on integrated “Zero Waste” biorefinery utilising all fractions of willow feedstock for the production of biochemicals and renewable energy. This project aims to investigate the crude and processed bark ...


Effect Of Uracil Dna Glycosylase Activity On The Efficacy Of Thymidylate Synthase Inhibitor/Hdac Inhibitor Combination Therapies In Colon Cancer, Rashmi Kulkarni, Brian P Weiser 2022 Rowan University

Effect Of Uracil Dna Glycosylase Activity On The Efficacy Of Thymidylate Synthase Inhibitor/Hdac Inhibitor Combination Therapies In Colon Cancer, Rashmi Kulkarni, Brian P Weiser

Stratford Campus Research Day

Human uracil DNA glycosylase (UNG2) is responsible for removing uracil bases from DNA and initiates base excision repair pathways. Accumulation of uracil or its fluorinated analogs in DNA is one of the killing mechanisms of thymidylate synthase (TS) inhibitors in cancer cells, and depletion of UNG2 often enhances the toxicity of these anticancer drugs. We tested the effect of UNG2 KO on the efficacy of multiple TS inhibitors (5-fluorouracil, fluorodeoxyuridine, and pemetrexed) and we determined that, except for 5-fluorouracil, all other TS inhibitors were significantly more potent in UNG2 KO cells compared to wild-type HT29 cells. Interestingly, UNG2 protein levels ...


Interactions Among Endothelial Nitric Oxide Synthase, Cardiovascular System, And Nociception During Physiological And Pathophysiological States, Niribili Sarmah, Andromeda M. Nauli, Ahmmed Ally, Surya M. Nauli 2022 Arkansas College of Osteopathic Medicine

Interactions Among Endothelial Nitric Oxide Synthase, Cardiovascular System, And Nociception During Physiological And Pathophysiological States, Niribili Sarmah, Andromeda M. Nauli, Ahmmed Ally, Surya M. Nauli

Pharmacy Faculty Articles and Research

Nitric oxide synthase (NOS) plays important roles within the cardiovascular system in physiological states as well as in pathophysiologic and specific cardiovascular (CV) disease states, such as hypertension (HTN), arteriosclerosis, and cerebrovascular accidents. This review discusses the roles of the endothelial NOS (eNOS) and its effect on cardiovascular responses that are induced by nociceptive stimuli. The roles of eNOS enzyme in modulating CV functions while experiencing pain will be discussed. Nociception, otherwise known as the subjective experience of pain through sensory receptors, termed “nociceptors”, can be stimulated by various external or internal stimuli. In turn, events of various cascade pathways ...


Computer Simulations And Network-Based Profiling Of Binding And Allosteric Interactions Of Sars-Cov-2 Spike Variant Complexes And The Host Receptor: Dissecting The Mechanistic Effects Of The Delta And Omicron Mutations, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan 2022 Chapman University

Computer Simulations And Network-Based Profiling Of Binding And Allosteric Interactions Of Sars-Cov-2 Spike Variant Complexes And The Host Receptor: Dissecting The Mechanistic Effects Of The Delta And Omicron Mutations, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we combine all-atom MD simulations and comprehensive mutational scanning of S-RBD complexes with the angiotensin-converting enzyme 2 (ACE2) host receptor in the native form as well as the S-RBD Delta and Omicron variants to (a) examine the differences in the dynamic signatures of the S-RBD complexes and (b) identify the critical binding hotspots and sensitivity of the mutational positions. We also examined the differences in allosteric interactions and communications in the S-RBD complexes for the Delta and Omicron variants. Through the perturbation-based scanning of the allosteric propensities of the SARS-CoV-2 S-RBD residues and dynamics-based network centrality and ...


Discovering The Role Of Repeat Sequences In Regulation Of The Phaz Gene In Streptomyces Sp. Sfb5a, Harrison Senter, Stephen Baron 2022 Bridgewater College

Discovering The Role Of Repeat Sequences In Regulation Of The Phaz Gene In Streptomyces Sp. Sfb5a, Harrison Senter, Stephen Baron

Honors Projects

Streptomyces sp. SFB5A is an actinomycete (filamentous bacterium) that degrades PHB using an extracellular PHB depolymerase. PHB depolymerase synthesis is induced by growth on PHB and repressed by glucose (or other preferred carbon sources)2, which suggests that there is transcriptional regulation of its corresponding gene, phaZ. Binding sites are suspected to be the repeat sequences found in the phaZ gene. There are 3 different sets of primers that can be made in order to emphasize specific functional repeats while disrupting the functionality of others. The goal of the project is to transform Streptomyces sp. 5A with constructs containing a ...


Late-Stage Chemoenzymatic Installation Of Hydroxy-Bearing Allyl Moiety On The Indole Ring Of Tryptophan-Containing Peptides, Nagaraju Mupparapu, Lauren Brewster, Katrina F. Ostrom, Sherif I. Elshahawi 2022 Chapman University

Late-Stage Chemoenzymatic Installation Of Hydroxy-Bearing Allyl Moiety On The Indole Ring Of Tryptophan-Containing Peptides, Nagaraju Mupparapu, Lauren Brewster, Katrina F. Ostrom, Sherif I. Elshahawi

Pharmacy Faculty Articles and Research

The late-stage functionalization of indole- and tryptophan-containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. Here, the synthesis of two hydroxy-bearing allyl pyrophosphates is described. A chemoenzymatic method is demonstrated which uses a promiscuous indole prenyltransferase enzyme to install a dual reactive hydroxy-bearing allyl moiety directly on the indole ring of tryptophan-containing peptides. This is the first report of late-stage indole modifications with this reactive group.


Pathogen Infection And Cholesterol Deficiency Activate The C. Elegans P38 Immune Pathway Through A Tir-1/Sarm1 Phase Transition, Nicholas D. Peterson, Janneke D. Icso, J. Elizabeth Salisbury, Tomas Rodriguez, Paul R. Thompson, Read Pukkila-Worley 2022 UMass Chan Medical School

Pathogen Infection And Cholesterol Deficiency Activate The C. Elegans P38 Immune Pathway Through A Tir-1/Sarm1 Phase Transition, Nicholas D. Peterson, Janneke D. Icso, J. Elizabeth Salisbury, Tomas Rodriguez, Paul R. Thompson, Read Pukkila-Worley

Thompson Lab Publications

Intracellular signaling regulators can be concentrated into membrane-free, higher ordered protein assemblies to initiate protective responses during stress - a process known as phase transition. Here, we show that a phase transition of the Caenorhabditis elegans Toll/interleukin-1 receptor domain protein (TIR-1), an NAD(+) glycohydrolase homologous to mammalian sterile alpha and TIR motif-containing 1 (SARM1), underlies p38 PMK-1 immune pathway activation in C. elegans intestinal epithelial cells. Through visualization of fluorescently labeled TIR-1/SARM1 protein, we demonstrate that physiologic stresses, both pathogen and non-pathogen, induce multimerization of TIR-1/SARM1 into visible puncta within intestinal epithelial cells. In vitro enzyme kinetic analyses ...


The Scaffold-Dependent Function Of Ripk1 In Dendritic Cells Promotes Injury-Induced Colitis, Kenta Moriwaki, Christa Park, Kazuha Koyama, Sakthi Balaji, Kohei Kita, Ryoko Yagi, Sachiko Komazawa-Sakon, Manami Semba, Tatsuya Asuka, Hiroyasu Nakano, Yoshihiro Kamada, Eiji Miyoshi, Francis K. M. Chan 2022 Toho University

The Scaffold-Dependent Function Of Ripk1 In Dendritic Cells Promotes Injury-Induced Colitis, Kenta Moriwaki, Christa Park, Kazuha Koyama, Sakthi Balaji, Kohei Kita, Ryoko Yagi, Sachiko Komazawa-Sakon, Manami Semba, Tatsuya Asuka, Hiroyasu Nakano, Yoshihiro Kamada, Eiji Miyoshi, Francis K. M. Chan

Open Access Publications by UMass Chan Authors

Receptor interacting protein kinase 1 (RIPK1) is a cytosolic multidomain protein that controls cell life and death. While RIPK1 promotes cell death through its kinase activity, it also functions as a scaffold protein to promote cell survival by inhibiting FADD-caspase 8-dependent apoptosis and RIPK3-MLKL-dependent necroptosis. This pro-survival function is highlighted by excess cell death and perinatal lethality in Ripk1(-/-) mice. Recently, loss of function mutation of RIPK1 was found in patients with immunodeficiency and inflammatory bowel diseases. Hematopoietic stem cell transplantation restored not only immunodeficiency but also intestinal inflammatory pathology, indicating that RIPK1 in hematopoietic cells is critical to maintain ...


Endothelial Nitric Oxide Synthase (Enos) And The Cardiovascular System: In Physiology And In Disease States, N Tran, T Garcia, M Aniqa, S Ali, A Ally, Surya M. Nauli 2022 Arkansas College of Osteopathic Medicine

Endothelial Nitric Oxide Synthase (Enos) And The Cardiovascular System: In Physiology And In Disease States, N Tran, T Garcia, M Aniqa, S Ali, A Ally, Surya M. Nauli

Pharmacy Faculty Articles and Research

Endothelial nitric oxide synthase (eNOS) plays a critical role in regulating and maintaining a healthy cardiovascular system. The importance of eNOS can be emphasized from the genetic polymorphisms of the eNOS gene, uncoupling of eNOS dimerization, and its numerous signaling regulations. The activity of eNOS on the cardiac myocytes, vasculature, and the central nervous system are discussed. The effects of eNOS on the sympathetic autonomic nervous system (SANS) and the parasympathetic autonomic nervous system (PANS), both of which profoundly influence the cardiovascular system, will be elaborated. The relationship between the eNOS protein with cardiovascular autonomic reflexes such as the baroreflex ...


Structural Basis Of The Super- And Hyper-Relaxed States Of Myosin Ii, Roger W. Craig, Raul A. Padron 2021 UMass Chan Medical School

Structural Basis Of The Super- And Hyper-Relaxed States Of Myosin Ii, Roger W. Craig, Raul A. Padron

Radiology Publications

Super-relaxation is a state of muscle thick filaments in which ATP turnover by myosin is much slower than that of myosin II in solution. This inhibited state, in equilibrium with a faster (relaxed) state, is ubiquitous and thought to be fundamental to muscle function, acting as a mechanism for switching off energy-consuming myosin motors when they are not being used. The structural basis of super-relaxation is usually taken to be a motif formed by myosin in which the two heads interact with each other and with the proximal tail forming an interacting-heads motif, which switches the heads off. However, recent ...


A Review Of Calcineurin Biophysics With Implications For Cardiac Physiology, Ryan B. Williams 2021 Mississippi State University

A Review Of Calcineurin Biophysics With Implications For Cardiac Physiology, Ryan B. Williams

Theses and Dissertations

Calmodulin is a prevalent calcium sensing protein found in all cells. Three genes exist for calmodulin and all three of these genes encode for the exact same protein sequence. Recently mutations in the amino acid sequence of calmodulin have been identified in living human patients. Thus far, patients harboring these mutations in the calmodulin sequence have only displayed an altered cardiac related phenotype. Calcineurin is involved in many key physiological processes and its activity is regulated by calcium and calmodulin. In order to assess whether or not calcineurin contributes to calmodulinopathy (a pathological state arising from dysfunctional calmodulin), a comprehensive ...


Deciphering The Molecular Mechanism Of Hcv Protease Inhibitor Fluorination As A General Approach To Avoid Drug Resistance [Preprint], Jacqueto Zephyr, Nageswara Rao Desaboini, Sang V. Vo, Mina Henes, Klajdi Kosovrasti, Ashley N. Matthew, Adam K. Hedger, Jennifer Timm, Elise T. Chan, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer 2021 University of Massachusetts Medical School

Deciphering The Molecular Mechanism Of Hcv Protease Inhibitor Fluorination As A General Approach To Avoid Drug Resistance [Preprint], Jacqueto Zephyr, Nageswara Rao Desaboini, Sang V. Vo, Mina Henes, Klajdi Kosovrasti, Ashley N. Matthew, Adam K. Hedger, Jennifer Timm, Elise T. Chan, Akbar Ali, Nese Kurt Yilmaz, Celia A. Schiffer

UMass Chan Medical School Faculty Publications

Third generation Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs), glecaprevir and voxilaprevir, are highly effective across genotypes and against many resistant variants. Unlike earlier PIs, these compounds have fluorine substitutions on the P2-P4 macrocycle and P1 moieties. Fluorination has long been used in medicinal chemistry as a strategy to improve physicochemical properties and potency. However, the molecular basis by which fluorination improves potency and resistance profile of HCV NS3/4A PIs is not well understood. To systematically analyze the contribution of fluorine substitutions to inhibitor potency and resistance profile, we used a multi-disciplinary approach involving inhibitor design and ...


An Rnai Therapeutic Targeting Hepatic Dgat2 In A Genetically Obese Mouse Model Of Nonalcoholic Steatohepatitis, Batuhan Yenilmez, Nicole Wetoska, Mark Kelly, Dimas Echeverria, Kyounghee Min, Lawrence M. Lifshitz, Julia F. Alterman, Matthew R. Hassler, Samuel R. Hildebrand, Chloe DiMarzio, Nicholas McHugh, Lorenc Vangjeli, Jacquelyn Sousa, Michael A. Brehm, Anastasia Khvorova, Michael P. Czech 2021 University of Massachusetts Medical School

An Rnai Therapeutic Targeting Hepatic Dgat2 In A Genetically Obese Mouse Model Of Nonalcoholic Steatohepatitis, Batuhan Yenilmez, Nicole Wetoska, Mark Kelly, Dimas Echeverria, Kyounghee Min, Lawrence M. Lifshitz, Julia F. Alterman, Matthew R. Hassler, Samuel R. Hildebrand, Chloe Dimarzio, Nicholas Mchugh, Lorenc Vangjeli, Jacquelyn Sousa, Michael A. Brehm, Anastasia Khvorova, Michael P. Czech

UMass Center for Clinical and Translational Science Supported Publications

Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single ...


Systematic Review Of The Receptor Tyrosine Kinase Superfamily In Neuroblastoma Pathophysiology, Esteban Javier Rozen, Jason Matthew Shohet 2021 UMass Chan Medical School

Systematic Review Of The Receptor Tyrosine Kinase Superfamily In Neuroblastoma Pathophysiology, Esteban Javier Rozen, Jason Matthew Shohet

Open Access Publications by UMass Chan Authors

BACKGROUND: Neuroblastoma is a devastating disease accounting for 15% of all childhood cancer deaths. Yet, our understanding of key molecular drivers such as receptor tyrosine kinases (RTKs) in this pathology remains poorly clarified. Here, we provide a systematic analysis of the RTK superfamily in the context of neuroblastoma pathogenesis.

METHODS: Statistical correlations for all RTK family members' expression to neuroblastoma patient survival across 10 independent patient cohorts were annotated, synthesized, and ranked using the R2: Genomics Analysis and Visualization Platform. Gene expression of selected members across different cancer cell lines was further analyzed in the Cancer Cell Line Encyclopedia, part ...


Camkii Binds Both Substrates And Activators At The Active Site [Preprint], Can Ozden, Roman Sloutsky, Tomohiro Mitsugi, Nicholas Santos, Emily Agnello, Christl Gaubitz, Joshua Foster, Emily Lapinskas, Edward A. Esposito, Takeo Saneyoshi, Brian A. Kelch, Scott C. Garman, Yasunori Hayashi, Margaret M. Stratton 2021 University of Massachusetts Amherst

Camkii Binds Both Substrates And Activators At The Active Site [Preprint], Can Ozden, Roman Sloutsky, Tomohiro Mitsugi, Nicholas Santos, Emily Agnello, Christl Gaubitz, Joshua Foster, Emily Lapinskas, Edward A. Esposito, Takeo Saneyoshi, Brian A. Kelch, Scott C. Garman, Yasunori Hayashi, Margaret M. Stratton

UMass Chan Medical School Faculty Publications

Ca2+/calmodulin dependent protein kinase II (CaMKII) is a signaling protein that is required for long-term memory formation. Ca2+/CaM activates CaMKII by binding to its regulatory segment, thereby freeing the substrate binding site. Despite having a large variety of interaction partners, the specificity of CaMKII interactions have not been structurally well-characterized. One exceptional feature of this kinase is that interaction with specific binding partners persistently activates CaMKII. To address the molecular details of this, we solved X-ray crystal structures of the CaMKII kinase domain bound to four different binding partners that modulate CaMKII activity in different ways ...


Applicability Of Small-Molecule Inhibitors In The Study Of Peptidyl Arginine Deiminase 2 (Pad2) And Pad4, Maria Teresa. Martin Monreal, Alexandra Stripp Rebak, Laura Massarenti, Santanu Mondal, Ladislav Senolt, Niels Odum, Michael L. Nielsen, Paul R. Thompson, Claus H. Nielsen, Dres Damgaard 2021 Copenhagen University Hospital

Applicability Of Small-Molecule Inhibitors In The Study Of Peptidyl Arginine Deiminase 2 (Pad2) And Pad4, Maria Teresa. Martin Monreal, Alexandra Stripp Rebak, Laura Massarenti, Santanu Mondal, Ladislav Senolt, Niels Odum, Michael L. Nielsen, Paul R. Thompson, Claus H. Nielsen, Dres Damgaard

UMass Chan Medical School Faculty Publications

Citrullination, the conversion of peptidyl-arginine into peptidyl-citrulline, is involved in the breakage of self-tolerance in anti-CCP-positive rheumatoid arthritis. This reaction is catalyzed by peptidyl arginine deiminases (PADs), of which PAD2 and PAD4 are thought to play key pathogenic roles. Small-molecule PAD inhibitors such as the pan-PAD inhibitor BB-Cl-amidine, the PAD2-specific inhibitor AFM-30a, and the PAD4-specific inhibitor GSK199 hold therapeutic potential and are useful tools in studies of citrullination. Using an ELISA based on the citrullination of fibrinogen, we found that AFM-30a inhibited the catalytic activity of PADs derived from live PMNs or lysed PBMCs and PMNs and of PADs in ...


Dcp2 C-Terminal Cis-Binding Elements Control Selective Targeting Of The Decapping Enzyme By Forming Distinct Decapping Complexes [Preprint], Feng He, Chan Wu, Allan S. Jacobson 2021 University of Massachusetts Medical School

Dcp2 C-Terminal Cis-Binding Elements Control Selective Targeting Of The Decapping Enzyme By Forming Distinct Decapping Complexes [Preprint], Feng He, Chan Wu, Allan S. Jacobson

UMass Chan Medical School Faculty Publications

A single Dcp1-Dcp2 decapping enzyme targets diverse classes of yeast mRNAs for decapping-dependent 5’ to 3’ decay, but the molecular mechanisms controlling selective mRNA targeting by the enzyme remain elusive. Through extensive genetic analyses we uncover cis-regulatory elements in the Dcp2 C-terminal domain that control selective targeting of the decapping enzyme by forming distinct decapping complexes. Two Upf1-binding motifs target the decapping enzyme to NMD substrates, and a single Edc3-binding motif targets both Edc3 and Dhh1 substrates. Pat1-binding leucine-rich motifs target Edc3 and Dhh1 substrates under selective conditions. Although it functions as a unique targeting component of specific complexes ...


Activity-Based Hydrazine Probes For Protein Profiling Of Electrophilic Functionality In Therapeutic Targets, Zongtao Lin, Xie Wang, Katelyn A. Bustin, Kyosuke Shishikura, Nate R. McKnight, Lin He, Radu M. Suciu, Kai Hu, Xian Han, Mina Ahmadi, Erika J. Olson, William H. Parsons, Megan L. Matthews 2021 University of Pennsylvania

Activity-Based Hydrazine Probes For Protein Profiling Of Electrophilic Functionality In Therapeutic Targets, Zongtao Lin, Xie Wang, Katelyn A. Bustin, Kyosuke Shishikura, Nate R. Mcknight, Lin He, Radu M. Suciu, Kai Hu, Xian Han, Mina Ahmadi, Erika J. Olson, William H. Parsons, Megan L. Matthews

Open Access Publications by UMass Chan Authors

Most known probes for activity-based protein profiling (ABPP) use electrophilic groups that tag a single type of nucleophilic amino acid to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electrophilic enzyme cofactors, transient intermediates, and labile regulatory modifications, but ABPP probes for such species are underdeveloped. Here, we describe a versatile class of probes for this less charted hemisphere of the proteome. The use of an electron-rich hydrazine as the common chemical modifier enables covalent targeting of multiple, pharmacologically important classes of enzymes bearing diverse organic and inorganic cofactors. Probe attachment occurs by both polar ...


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