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Emily R. Derbyshire

Associate Professor of Chemistry
Chemistry
3218 French Science Center, Durham, NC 27708

Selected Publications


Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome.

Journal Article Cell Chem Biol · March 13, 2024 The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp9 ... Full text Link to item Cite

Toxoplasma and Plasmodium associate with host Arfs during infection.

Journal Article mSphere · March 2024 The apicomplexans Toxoplasma gondii and Plasmodium are intracellular parasites that reside within a host-derived compartment termed the parasitophorous vacuole (PV). During infection, the parasites must acquire critical host resources and tra ... Full text Cite

Characterization of 2,4-Dianilinopyrimidines Against Five P. falciparum Kinases PfARK1, PfARK3, PfNEK3, PfPK9, and PfPKB.

Journal Article ACS medicinal chemistry letters · December 2023 Plasmodium kinases are increasingly recognized as potential novel antiplasmodial targets for the treatment of malaria, but only a small subset of these kinases have had structure-activity relationship (SAR) campaigns reported. Herein we report the d ... Full text Cite

Examination of Secondary Metabolite Biosynthesis in Apicomplexa.

Journal Article Chembiochem : a European journal of chemical biology · September 2023 Natural product discovery has traditionally relied on the isolation of small molecules from producing species, but genome-sequencing technology and advances in molecular biology techniques have expanded efforts to a wider array of organisms. Protists repre ... Full text Cite

Exploring the Chain Release Mechanism from an Atypical Apicomplexan Polyketide Synthase.

Journal Article Biochemistry · September 2023 Polyketide synthases (PKSs) are megaenzymes that form chemically diverse polyketides and are found within the genomes of nearly all classes of life. We recently discovered the type I PKS from the apicomplexan parasite Toxoplasma gondii, TgPKS ... Full text Cite

Labeling strategies to track protozoan parasite proteome dynamics.

Journal Article Current opinion in chemical biology · August 2023 Intracellular protozoan parasites are responsible for wide-spread infectious diseases. These unicellular pathogens have complex, multi-host life cycles, which present challenges for investigating their basic biology and for discovering vulnerabilities that ... Full text Cite

Synthesis and activity of β-carboline antimalarials targeting the Plasmodium falciparum heat shock 90 protein.

Journal Article Bioorganic & medicinal chemistry letters · August 2023 A collection of β-carbolines based on the natural product harmine, a compound known to target the heat shock 90 protein of Plasmodium falciparum, was synthesized and tested for antimalarial activity and potential toxicity. Several of these novel compounds ... Full text Cite

Characterization of Unexpected Self-Acylation Activity of Acyl Carrier Proteins in a Modular Type I Apicomplexan Polyketide Synthase.

Journal Article ACS chemical biology · April 2023 Natural products play critical roles as antibiotics, anticancer therapeutics, and biofuels. Polyketides are a distinct natural product class of structurally diverse secondary metabolites that are synthesized by polyketide synthases (PKSs). The biosynthetic ... Full text Cite

Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore.

Journal Article European journal of medicinal chemistry · March 2023 Malaria is a devastating disease that causes significant global morbidity and mortality. The rise of drug resistance against artemisinin-based combination therapy demonstrates the necessity to develop alternative antimalarials with novel mechanisms of acti ... Full text Cite

Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro.

Journal Article Journal of medicinal chemistry · October 2022 Essential plasmodial kinases PfGSK3 and PfPK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of IKK16 as a dual PfGSK3/PfPK6 inhibitor ac ... Full text Cite

Cut it out! A CRISPR-Cas9 screen identifies host regulators of the Plasmodium liver stage.

Journal Article Cell chemical biology · September 2022 In this issue of Cell Chemical Biology, Vijayan and colleagues identify host factors integral for Plasmodium liver-stage infection using a whole-genome CRISPR-Cas9 knockout screen. Their efforts reveal that liver-stage parasites redistribute host microtubu ... Full text Cite

Random Forest Model Predictions Afford Dual-Stage Antimalarial Agents.

Journal Article ACS infectious diseases · August 2022 The need for novel antimalarials is apparent given the continuing disease burden worldwide, despite significant drug discovery advances from the bench to the bedside. In particular, small-molecule agents with potent efficacy against both the liver and bloo ... Full text Cite

Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance.

Journal Article Nature communications · August 2022 The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world's most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl ... Full text Cite

Plasmodium's fight for survival: escaping elimination while acquiring nutrients.

Journal Article Trends in parasitology · July 2022 Plasmodium parasites extensively alter their host hepatocyte to evade host detection and support an unprecedented replication rate. Host cell manipulation includes association with the host early and late endomembrane systems, where Plasmodium accesses nut ... Full text Cite

Erratum: A single amino acid residue controls acyltransferase activity in a polyketide synthase from Toxoplasma gondii.

Journal Article iScience · July 2022 [This corrects the article DOI: 10.1016/j.isci.2022.104443.]. ... Full text Cite

A single amino acid residue controls acyltransferase activity in a polyketide synthase from Toxoplasma gondii.

Journal Article iScience · June 2022 Type I polyketide synthases (PKSs) are multidomain, multimodule enzymes capable of producing complex polyketide metabolites. These modules contain an acyltransferase (AT) domain, which selects acyl-CoA substrates to be incorporated into the metabolite scaf ... Full text Cite

Chemoproteomics for Plasmodium Parasite Drug Target Discovery.

Journal Article Chembiochem : a European journal of chemical biology · August 2021 Emerging Plasmodium parasite drug resistance is threatening progress towards malaria control and elimination. While recent efforts in cell-based, high-throughput drug screening have produced first-in-class drugs with promising activities against different ... Full text Cite

Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice.

Journal Article Nat Commun · March 17, 2021 GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia fol ... Full text Link to item Cite

Characterization of the Tubovesicular Network in Plasmodium vivax Liver Stage Hypnozoites and Schizonts.

Journal Article Frontiers in cellular and infection microbiology · January 2021 Plasmodium is a genus of apicomplexan parasites which replicate in the liver before causing malaria. Plasmodium vivax can also persist in the liver as dormant hypnozoites and cause clinical relapse upon activation, but the molecular mechanism ... Full text Cite

Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death.

Journal Article eLife · September 2020 Featured Publication Phosphatidylinositol 3-phosphate (PI(3)P) levels in Plasmodium falciparum correlate with tolerance to cellular stresses caused by artemisinin and environmental factors. However, PI(3)P function during the Plasmodium stress response was unknow ... Full text Cite

Selective targeting of Plasmodium falciparum Hsp90 disrupts the 26S proteasome.

Journal Article Cell Chem Biol · March 13, 2024 The molecular chaperone heat shock protein 90 (Hsp90) has an essential but largely undefined role in maintaining proteostasis in Plasmodium falciparum, the most lethal malaria parasite. Herein, we identify BX-2819 and XL888 as potent P. falciparum (Pf)Hsp9 ... Full text Link to item Cite

Toxoplasma and Plasmodium associate with host Arfs during infection.

Journal Article mSphere · March 2024 The apicomplexans Toxoplasma gondii and Plasmodium are intracellular parasites that reside within a host-derived compartment termed the parasitophorous vacuole (PV). During infection, the parasites must acquire critical host resources and tra ... Full text Cite

Characterization of 2,4-Dianilinopyrimidines Against Five P. falciparum Kinases PfARK1, PfARK3, PfNEK3, PfPK9, and PfPKB.

Journal Article ACS medicinal chemistry letters · December 2023 Plasmodium kinases are increasingly recognized as potential novel antiplasmodial targets for the treatment of malaria, but only a small subset of these kinases have had structure-activity relationship (SAR) campaigns reported. Herein we report the d ... Full text Cite

Examination of Secondary Metabolite Biosynthesis in Apicomplexa.

Journal Article Chembiochem : a European journal of chemical biology · September 2023 Natural product discovery has traditionally relied on the isolation of small molecules from producing species, but genome-sequencing technology and advances in molecular biology techniques have expanded efforts to a wider array of organisms. Protists repre ... Full text Cite

Exploring the Chain Release Mechanism from an Atypical Apicomplexan Polyketide Synthase.

Journal Article Biochemistry · September 2023 Polyketide synthases (PKSs) are megaenzymes that form chemically diverse polyketides and are found within the genomes of nearly all classes of life. We recently discovered the type I PKS from the apicomplexan parasite Toxoplasma gondii, TgPKS ... Full text Cite

Labeling strategies to track protozoan parasite proteome dynamics.

Journal Article Current opinion in chemical biology · August 2023 Intracellular protozoan parasites are responsible for wide-spread infectious diseases. These unicellular pathogens have complex, multi-host life cycles, which present challenges for investigating their basic biology and for discovering vulnerabilities that ... Full text Cite

Synthesis and activity of β-carboline antimalarials targeting the Plasmodium falciparum heat shock 90 protein.

Journal Article Bioorganic & medicinal chemistry letters · August 2023 A collection of β-carbolines based on the natural product harmine, a compound known to target the heat shock 90 protein of Plasmodium falciparum, was synthesized and tested for antimalarial activity and potential toxicity. Several of these novel compounds ... Full text Cite

Characterization of Unexpected Self-Acylation Activity of Acyl Carrier Proteins in a Modular Type I Apicomplexan Polyketide Synthase.

Journal Article ACS chemical biology · April 2023 Natural products play critical roles as antibiotics, anticancer therapeutics, and biofuels. Polyketides are a distinct natural product class of structurally diverse secondary metabolites that are synthesized by polyketide synthases (PKSs). The biosynthetic ... Full text Cite

Discovery of potent Plasmodium falciparum protein kinase 6 (PfPK6) inhibitors with a type II inhibitor pharmacophore.

Journal Article European journal of medicinal chemistry · March 2023 Malaria is a devastating disease that causes significant global morbidity and mortality. The rise of drug resistance against artemisinin-based combination therapy demonstrates the necessity to develop alternative antimalarials with novel mechanisms of acti ... Full text Cite

Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro.

Journal Article Journal of medicinal chemistry · October 2022 Essential plasmodial kinases PfGSK3 and PfPK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of IKK16 as a dual PfGSK3/PfPK6 inhibitor ac ... Full text Cite

Cut it out! A CRISPR-Cas9 screen identifies host regulators of the Plasmodium liver stage.

Journal Article Cell chemical biology · September 2022 In this issue of Cell Chemical Biology, Vijayan and colleagues identify host factors integral for Plasmodium liver-stage infection using a whole-genome CRISPR-Cas9 knockout screen. Their efforts reveal that liver-stage parasites redistribute host microtubu ... Full text Cite

Random Forest Model Predictions Afford Dual-Stage Antimalarial Agents.

Journal Article ACS infectious diseases · August 2022 The need for novel antimalarials is apparent given the continuing disease burden worldwide, despite significant drug discovery advances from the bench to the bedside. In particular, small-molecule agents with potent efficacy against both the liver and bloo ... Full text Cite

Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance.

Journal Article Nature communications · August 2022 The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world's most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl ... Full text Cite

Plasmodium's fight for survival: escaping elimination while acquiring nutrients.

Journal Article Trends in parasitology · July 2022 Plasmodium parasites extensively alter their host hepatocyte to evade host detection and support an unprecedented replication rate. Host cell manipulation includes association with the host early and late endomembrane systems, where Plasmodium accesses nut ... Full text Cite

Erratum: A single amino acid residue controls acyltransferase activity in a polyketide synthase from Toxoplasma gondii.

Journal Article iScience · July 2022 [This corrects the article DOI: 10.1016/j.isci.2022.104443.]. ... Full text Cite

A single amino acid residue controls acyltransferase activity in a polyketide synthase from Toxoplasma gondii.

Journal Article iScience · June 2022 Type I polyketide synthases (PKSs) are multidomain, multimodule enzymes capable of producing complex polyketide metabolites. These modules contain an acyltransferase (AT) domain, which selects acyl-CoA substrates to be incorporated into the metabolite scaf ... Full text Cite

Chemoproteomics for Plasmodium Parasite Drug Target Discovery.

Journal Article Chembiochem : a European journal of chemical biology · August 2021 Emerging Plasmodium parasite drug resistance is threatening progress towards malaria control and elimination. While recent efforts in cell-based, high-throughput drug screening have produced first-in-class drugs with promising activities against different ... Full text Cite

Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice.

Journal Article Nat Commun · March 17, 2021 GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia fol ... Full text Link to item Cite

Characterization of the Tubovesicular Network in Plasmodium vivax Liver Stage Hypnozoites and Schizonts.

Journal Article Frontiers in cellular and infection microbiology · January 2021 Plasmodium is a genus of apicomplexan parasites which replicate in the liver before causing malaria. Plasmodium vivax can also persist in the liver as dormant hypnozoites and cause clinical relapse upon activation, but the molecular mechanism ... Full text Cite

Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death.

Journal Article eLife · September 2020 Featured Publication Phosphatidylinositol 3-phosphate (PI(3)P) levels in Plasmodium falciparum correlate with tolerance to cellular stresses caused by artemisinin and environmental factors. However, PI(3)P function during the Plasmodium stress response was unknow ... Full text Cite

A Systematic Analysis of Mosquito-Microbiome Biosynthetic Gene Clusters Reveals Antimalarial Siderophores that Reduce Mosquito Reproduction Capacity.

Journal Article Cell chemical biology · July 2020 Featured Publication Advances in infectious disease control strategies through genetic manipulation of insect microbiomes have heightened interest in microbially produced small molecules within mosquitoes. Herein, 33 mosquito-associated bacterial genomes were mined and over 70 ... Full text Cite

Plasmodium vivax Liver and Blood Stages Recruit the Druggable Host Membrane Channel Aquaporin-3.

Journal Article Cell chemical biology · June 2020 Featured Publication Plasmodium vivax infects hepatocytes to form schizonts that cause blood infection, or dormant hypnozoites that can persist for months in the liver before leading to relapsing blood infections. The molecular processes that drive P. vivax schizont and hypnoz ... Full text Cite

Coculturing of Mosquito-Microbiome Bacteria Promotes Heme Degradation in Elizabethkingia anophelis.

Journal Article Chembiochem : a European journal of chemical biology · May 2020 Anopheles mosquito microbiomes are intriguing ecological niches. Within the gut, microbes adapt to oxidative stress due to heme and iron after blood meals. Although metagenomic sequencing has illuminated spatial and temporal fluxes of microbiome population ... Full text Cite

Tafenoquine: A Step toward Malaria Elimination.

Journal Article Biochemistry · March 2020 There is a pressing need for compounds with broad-spectrum activity against malaria parasites at various life cycle stages to achieve malaria elimination. However, this goal cannot be accomplished without targeting the tenacious dormant liver-stage hypnozo ... Full text Cite

Plasmodium chaperonin TRiC/CCT identified as a target of the antihistamine clemastine using parallel chemoproteomic strategy.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · March 2020 The antihistamine clemastine inhibits multiple stages of the Plasmodium parasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied parallel chemoproteomic platforms to discover the ... Full text Cite

RNA-Seq Analysis Illuminates the Early Stages of Plasmodium Liver Infection.

Journal Article mBio · February 2020 The apicomplexan parasites Plasmodium spp. are the causative agents of malaria, a disease that poses a significant global health burden. Plasmodium spp. initiate infection of the human host by transforming and replicating within hepatocytes. ... Full text Cite

It's about Time: Insights into the Modes of Action of Antimalarials.

Journal Article Cell chemical biology · February 2020 In this issue of Cell Chemical Biology, Murithi et al. (2020) integrate stage-specific phenotypic screening and metabolomics to uncover modes of action of antimalarials. This work highlights compounds with potent activity against all asexual blood stages, ... Full text Cite

Investigating the Role of Class I Adenylate-Forming Enzymes in Natural Product Biosynthesis.

Journal Article ACS chemical biology · January 2020 Adenylate-forming enzymes represent one of the most important enzyme classes in biology, responsible for the activation of carboxylate substrates for biosynthetic modifications. The byproduct of the adenylate-forming enzyme acetyl-CoA synthetase, acetyl-Co ... Full text Cite

Linking Genes to Molecules in Eukaryotic Sources: An Endeavor to Expand Our Biosynthetic Repertoire.

Journal Article Molecules (Basel, Switzerland) · January 2020 The discovery of natural products continues to interest chemists and biologists for their utility in medicine as well as facilitating our understanding of signaling, pathogenesis, and evolution. Despite an attenuation in the discovery rate of new molecules ... Full text Cite

Discovery of Druggable Host Factors Critical to Plasmodium Liver-Stage Infection.

Journal Article Cell chemical biology · September 2019 Featured Publication Plasmodium parasites undergo an obligatory and asymptomatic developmental stage within the liver before infecting red blood cells to cause malaria. The hijacked host pathways critical to parasite infection during this hepatic phase remain poorly understood ... Full text Cite

Close the ring to break the cycle: tandem quinolone-alkyne-cyclisation gives access to tricyclic pyrrolo[1,2-a]quinolin-5-ones with potent anti-protozoal activity.

Journal Article Chemical communications (Cambridge, England) · June 2019 Expanding the chemical space of quinolones led to a tandem quinolone-alkyne-cyclisation reaction allowing chemoselective control of the synthesis of tricyclic pyrrolo[1,2-a]quinolin-5-ones. Importantly, we discovered anti-protozoal activity against Plasmod ... Full text Cite

Synthesis and Analysis of Natural-Product-Like Macrocycles by Tandem Oxidation/Oxa-Conjugate Addition Reactions.

Journal Article Chemistry (Weinheim an der Bergstrasse, Germany) · May 2019 As traditional small-molecule drug discovery programs focus on a relatively narrow range of chemical space, most human proteins are viewed as unreachable targets. Consequently, there is a strong interest in expanding the chemical space in drug discovery be ... Full text Cite

Plasmodium PK9 Inhibitors Promote Growth of Liver-Stage Parasites.

Journal Article Cell Chem Biol · March 21, 2019 There is a scarcity of pharmacological tools to interrogate protein kinase function in Plasmodium parasites, the causative agent of malaria. Among Plasmodium's protein kinases, those characterized as atypical represent attractive drug targets as they lack ... Full text Link to item Cite

In silico Screening and Evaluation of Plasmodium falciparum Protein Kinase 5 (PK5) Inhibitors.

Journal Article ChemMedChem · December 2018 An in silico screen of 350 000 commercially available compounds was conducted with an unbiased approach to identify potential malaria inhibitors that bind to the Plasmodium falciparum protein kinase 5 (PfPK5) ATP-binding site. PfPK5 is a cyclin-dependent k ... Full text Cite

Discovery of Antimicrobial Lipodepsipeptides Produced by a Serratia sp. within Mosquito Microbiomes.

Journal Article Chembiochem : a European journal of chemical biology · August 2018 The Anopheles mosquito that harbors the Plasmodium parasite contains a microbiota that can influence both the vector and the parasite. In recent years, insect-associated microbes have highlighted the untapped potential of exploiting interspecies interactio ... Full text Cite

Plasmodium parasite exploits host aquaporin-3 during liver stage malaria infection.

Journal Article PLoS Pathog · May 2018 Within the liver a single Plasmodium parasite transforms into thousands of blood-infective forms to cause malaria. Here, we use RNA-sequencing to identify host genes that are upregulated upon Plasmodium berghei infection of hepatocytes with the hypothesis ... Full text Open Access Link to item Cite

Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.

Journal Article Antimicrob Agents Chemother · April 2018 Malaria remains a global health burden partly due to Plasmodium parasite resistance to first-line therapeutics. The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an essential protein for blood-stage Plasmodium parasites, but details abou ... Full text Link to item Cite

Exploring the Untapped Biosynthetic Potential of Apicomplexan Parasites.

Journal Article Biochemistry · January 2018 Apicomplexan parasites encompass a diverse group of eukaryotic intracellular pathogens that infect various animal hosts to cause disease. Intriguingly, apicomplexans possess a unique organelle of algal origin, the apicoplast, which phylogenetically links t ... Full text Cite

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease.

Journal Article Cell Chem Biol · August 17, 2017 Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-T ... Full text Link to item Cite

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Journal Article Nature · October 2016 Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of syn ... Full text Cite

Current therapies and future possibilities for drug development against liver-stage malaria.

Journal Article The Journal of clinical investigation · June 2016 Malaria remains a global public health threat, with half of the world's population at risk. Despite numerous efforts in the past decade to develop new antimalarial drugs to surmount increasing resistance to common therapies, challenges remain in the expans ... Full text Cite

Exploration of Plasmodium Kinases

Conference FASEB JOURNAL · April 1, 2016 Link to item Cite

Exploration of Plasmodium Kinases

Conference FASEB JOURNAL · April 1, 2016 Link to item Cite

Discovery of Dual-Stage Malaria Inhibitors with New Targets.

Journal Article Antimicrobial agents and chemotherapy · December 2015 Malaria remains a major global health problem, with more than half of the world population at risk of contracting the disease and nearly a million deaths each year. Here, we report the discovery of inhibitors that target multiple stages of malaria parasite ... Full text Cite

The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs.

Journal Article Science translational medicine · May 2015 The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing nex ... Full text Cite

Chemical interrogation of the malaria kinome.

Journal Article Chembiochem : a European journal of chemical biology · September 2014 Malaria, an infectious disease caused by eukaryotic parasites of the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analys ... Full text Cite

Dihydroquinazolinone inhibitors of proliferation of blood and liver stage malaria parasites.

Journal Article Antimicrobial agents and chemotherapy · January 2014 Drugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. Evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria reveal ... Full text Cite

Closing in on a new treatment for sleeping sickness.

Journal Article eLife · July 2013 A chemoproteomics approach has been employed to identify a kinase that could be used as a druggable target in efforts to develop new treatments for African sleeping sickness. ... Full text Cite

Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide.

Journal Article The Journal of biological chemistry · December 2012 Nitric oxide (NO) signaling regulates key processes in cardiovascular physiology, specifically vasodilation, platelet aggregation, and leukocyte rolling. Soluble guanylate cyclase (sGC), the mammalian NO sensor, transduces an NO signal into the classical s ... Full text Cite

Antibiotic and antimalarial quinones from fungus-growing ant-associated Pseudonocardia sp.

Journal Article Journal of natural products · October 2012 Three new members of the angucycline class of antibiotics, pseudonocardones A-C (1-3), along with the known antibiotics 6-deoxy-8-O-methylrabelomycin (4) and X-14881 E (5) have been isolated from the culture of a Pseudonocardia strain associated with the f ... Full text Cite

Conformationally distinct five-coordinate heme-NO complexes of soluble guanylate cyclase elucidated by multifrequency electron paramagnetic resonance (EPR).

Journal Article Biochemistry · October 2012 Soluble guanylate cyclase (sGC) is a heme-containing enzyme that senses nitric oxide (NO). Formation of a heme Fe-NO complex is essential to sGC activation, and several spectroscopic techniques, including electron paramagnetic resonance (EPR) spectroscopy, ... Full text Cite

Liver-stage malaria parasites vulnerable to diverse chemical scaffolds.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · May 2012 Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. All high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis ... Full text Cite

Characterization of Plasmodium liver stage inhibition by halofuginone.

Journal Article ChemMedChem · May 2012 Malaria is a devastating parasitic disease that afflicts one-third of the world's population. Antimalarial drugs in common use address few targets, and their efficacy is being undermined by parasite resistance. Most therapeutics target blood-stage malaria, ... Full text Cite

Structure and regulation of soluble guanylate cyclase.

Journal Article Annual review of biochemistry · January 2012 Nitric oxide (NO) is an essential signaling molecule in biological systems. In mammals, the diatomic gas is critical to the cyclic guanosine monophosphate (cGMP) pathway as it functions as the primary activator of soluble guanylate cyclase (sGC). NO is syn ... Full text Cite

Identification and validation of tetracyclic benzothiazepines as Plasmodium falciparum cytochrome bc1 inhibitors.

Journal Article Chemistry & biology · December 2011 Here we report the discovery of tetracyclic benzothiazepines (BTZs) as highly potent and selective antimalarials along with the identification of the Plasmodium falciparum cytochrome bc(1) complex as the primary functional target of this novel compound cla ... Full text Cite

Probing domain interactions in soluble guanylate cyclase.

Journal Article Biochemistry · May 2011 Eukaryotic nitric oxide (NO) signaling involves modulation of cyclic GMP (cGMP) levels through activation of the soluble isoform of guanylate cyclase (sGC). sGC is a heterodimeric hemoprotein that contains a Heme-Nitric oxide and OXygen binding (H-NOX) dom ... Full text Cite

Soluble guanylate cyclase is activated differently by excess NO and by YC-1: resonance Raman spectroscopic evidence.

Journal Article Biochemistry · June 2010 Modulation of soluble guanylate cyclase (sGC) activity by nitric oxide (NO) involves two distinct steps. Low-level activation of sGC is achieved by the stoichiometric binding of NO (1-NO) to the heme cofactor, while much higher activation is achieved by th ... Full text Cite

Incorporation of tyrosine and glutamine residues into the soluble guanylate cyclase heme distal pocket alters NO and O2 binding.

Journal Article The Journal of biological chemistry · June 2010 Nitric oxide (NO) is the physiologically relevant activator of the mammalian hemoprotein soluble guanylate cyclase (sGC). The heme cofactor of alpha1beta1 sGC has a high affinity for NO but has never been observed to form a complex with oxygen. Introductio ... Full text Cite

Probing soluble guanylate cyclase activation by CO and YC-1 using resonance Raman spectroscopy.

Journal Article Biochemistry · May 2010 Soluble guanylate cyclase (sGC) is weakly activated by carbon monoxide (CO) but is significantly activated by the binding of YC-1 to the sGC-CO complex. In this report, resonance Raman (RR) spectroscopy was used to study selected sGC variants. Addition of ... Full text Cite

A nitric oxide/cysteine interaction mediates the activation of soluble guanylate cyclase.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · December 2009 Nitric oxide (NO) regulates a number of essential physiological processes by activating soluble guanylate cyclase (sGC) to produce the second messenger cGMP. The mechanism of NO sensing was previously thought to result exclusively from NO binding to the sG ... Full text Cite

Nucleotide regulation of soluble guanylate cyclase substrate specificity.

Journal Article Biochemistry · August 2009 Soluble guanylate cyclase (sGC) serves as a receptor for the signaling agent nitric oxide (NO). sGC synthesis of cGMP is regulated by NO, GTP, ATP, and allosteric activators such as YC-1. The guanylate cyclase activity and adenylate cyclase activity of ful ... Full text Cite

Biochemistry of soluble guanylate cyclase.

Journal Article Handbook of experimental pharmacology · January 2009 Nitric oxide (NO) functions in biology as both a critical cytotoxic agent and an essential signaling molecule. The toxicity of the diatomic gas has long been accepted; however, it was not known to be a signaling molecule until it was identified as the endo ... Full text Cite

The crystal structure of the catalytic domain of a eukaryotic guanylate cyclase.

Journal Article BMC structural biology · October 2008 BackgroundSoluble guanylate cyclases generate cyclic GMP when bound to nitric oxide, thereby linking nitric oxide levels to the control of processes such as vascular homeostasis and neurotransmission. The guanylate cyclase catalytic module, for wh ... Full text Cite

Characterization of two different five-coordinate soluble guanylate cyclase ferrous-nitrosyl complexes.

Journal Article Biochemistry · March 2008 Soluble guanylate cyclase (sGC), a hemoprotein, is the primary nitric oxide (NO) receptor in higher eukaryotes. The binding of NO to sGC leads to the formation of a five-coordinate ferrous-nitrosyl complex and a several hundred-fold increase in cGMP synthe ... Full text Cite

Butyl isocyanide as a probe of the activation mechanism of soluble guanylate cyclase. Investigating the role of non-heme nitric oxide.

Journal Article The Journal of biological chemistry · December 2007 Nitric oxide (NO) is a physiologically relevant activator of the hemoprotein soluble guanylate cyclase (sGC). In the presence of NO, sGC is activated several hundredfold above the basal level by a mechanism that remains to be elucidated. The heme ligand n- ... Full text Cite

Synthesis and evaluation of a phosphonate analogue of the soluble guanylate cyclase activator YC-1.

Journal Article Bioorganic & medicinal chemistry letters · September 2007 Soluble guanylate cyclase (sGC) is activated by the known benzylindazole derivative YC-1 [1-benzyl-3-(5'-hydroxymethyl-2'-furyl)-indazole]. YC-1 also acts synergistically with CO, activating sGC to a level comparable to that achieved upon binding of nitric ... Full text Cite

Dissociation of nitric oxide from soluble guanylate cyclase and heme-nitric oxide/oxygen binding domain constructs.

Journal Article The Journal of biological chemistry · January 2007 Regulation of soluble guanylate cyclase (sGC), the primary NO receptor, is linked to NO binding to the prosthetic heme group. Recent studies have demonstrated that the degree and duration of sGC activation depend on the presence and ratio of purine nucleot ... Full text Cite

Nitric oxide signaling: no longer simply on or off.

Journal Article Trends in biochemical sciences · April 2006 Nitric oxide (NO) triggers various physiological responses in numerous tissues by binding and activating soluble guanylate cyclase (sGC) to produce the second messenger cGMP. In vivo, basal NO/cGMP signaling maintains a resting state in target cells (for e ... Full text Cite

Characterization of nitrosoalkane binding and activation of soluble guanylate cyclase.

Journal Article Biochemistry · December 2005 Soluble guanylate cyclase (sGC) is the primary receptor for the signaling agent nitric oxide (NO). Electronic absorption and resonance Raman spectroscopy were used to show that nitrosoalkanes bind to the heme of sGC to form six-coordinate, low-spin complex ... Full text Cite