Publications by authors named "Boyu Zhao"

19 Publications

  • Page 1 of 1

A phosphate starvation response-centered network regulates mycorrhizal symbiosis.

Cell 2021 Oct 6. Epub 2021 Oct 6.

National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, SIBS, Chinese Academy of Sciences, Shanghai 200032, China. Electronic address:

To secure phosphorus (P) from soil, most land plants use a direct phosphate uptake pathway via root hairs and epidermis and an indirect phosphate uptake pathway via mycorrhizal symbiosis. The interaction between these two pathways is unclear. Here, we mapped a network between transcription factors and mycorrhizal symbiosis-related genes using Y1H. Intriguingly, this gene regulatory network is governed by the conserved P-sensing pathway, centered on phosphate starvation response (PHR) transcription factors. PHRs are required for mycorrhizal symbiosis and regulate symbiosis-related genes via the P1BS motif. SPX-domain proteins suppress OsPHR2-mediated induction of symbiosis-related genes and inhibit mycorrhizal infection. In contrast, plants overexpressing OsPHR2 show improved mycorrhizal infection and are partially resistant to P-mediated inhibition of symbiosis. Functional analyses of network nodes revealed co-regulation of hormonal signaling and mycorrhizal symbiosis. This network deciphers extensive regulation of mycorrhizal symbiosis by endogenous and exogenous signals and highlights co-option of the P-sensing pathway for mycorrhizal symbiosis.
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http://dx.doi.org/10.1016/j.cell.2021.09.030DOI Listing
October 2021

Plug-and-play aqueous electrochemical atom transfer radical polymerization.

Chem Commun (Camb) 2021 Apr 23;57(32):3897-3900. Epub 2021 Mar 23.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

A simplified 'plug-and-play' approach to aqueous electrochemical atom transfer radical polymerization (eATRP) has been developed. Well-controlled polymerization of PEGA (Đ = 1.17-1.31) is reported under potentiostatic (3-electrodes, undivided cell) and galvanostatic (2-electrodes, 6-steps) conditions.
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http://dx.doi.org/10.1039/d1cc01312bDOI Listing
April 2021

Identification of MLH2/hPMS1 dominant mutations that prevent DNA mismatch repair function.

Commun Biol 2020 12 10;3(1):751. Epub 2020 Dec 10.

DNA Repair Mechanisms and Cancer, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.

Inactivating mutations affecting key mismatch repair (MMR) components lead to microsatellite instability (MSI) and cancer. However, a number of patients with MSI-tumors do not present alterations in classical MMR genes. Here we discovered that specific missense mutations in the MutL homolog MLH2, which is dispensable for MMR, confer a dominant mutator phenotype in S. cerevisiae. MLH2 mutations elevated frameshift mutation rates, and caused accumulation of long-lasting nuclear MMR foci. Both aspects of this phenotype were suppressed by mutations predicted to prevent the binding of Mlh2 to DNA. Genetic analysis revealed that mlh2 dominant mutations interfere with both Exonuclease 1 (Exo1)-dependent and Exo1-independent MMR. Lastly, we demonstrate that a homolog mutation in human hPMS1 results in a dominant mutator phenotype. Our data support a model in which yeast Mlh1-Mlh2 or hMLH1-hPMS1 mutant complexes act as roadblocks on DNA preventing MMR, unraveling a novel mechanism that can account for MSI in human cancer.
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http://dx.doi.org/10.1038/s42003-020-01481-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730388PMC
December 2020

A genetic screen pinpoints ribonucleotide reductase residues that sustain dNTP homeostasis and specifies a highly mutagenic type of dNTP imbalance.

Nucleic Acids Res 2019 01;47(1):237-252

DNA Repair Mechanisms and Cancer, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany.

The balance and the overall concentration of intracellular deoxyribonucleoside triphosphates (dNTPs) are important determinants of faithful DNA replication. Despite the established fact that changes in dNTP pools negatively influence DNA replication fidelity, it is not clear why certain dNTP pool alterations are more mutagenic than others. As intracellular dNTP pools are mainly controlled by ribonucleotide reductase (RNR), and given the limited number of eukaryotic RNR mutations characterized so far, we screened for RNR1 mutations causing mutator phenotypes in Saccharomyces cerevisiae. We identified 24 rnr1 mutant alleles resulting in diverse mutator phenotypes linked in most cases to imbalanced dNTPs. Among the identified rnr1 alleles the strongest mutators presented a dNTP imbalance in which three out of the four dNTPs were elevated (dCTP, dTTP and dGTP), particularly if dGTP levels were highly increased. These rnr1 alleles caused growth defects/lethality in DNA replication fidelity-compromised backgrounds, and caused strong mutator phenotypes even in the presence of functional DNA polymerases and mismatch repair. In summary, this study pinpoints key residues that contribute to allosteric regulation of RNR's overall activity or substrate specificity. We propose a model that distinguishes between different dNTP pool alterations and provides a mechanistic explanation why certain dNTP imbalances are particularly detrimental.
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http://dx.doi.org/10.1093/nar/gky1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326808PMC
January 2019

A Comparison of Mandated, Presumed, and Explicit Consent Systems for Deceased Organ Donation among University Students in Singapore.

Ann Acad Med Singap 2018 02;47(2):74-77

Department of Anaesthesiology, Singapore General Hospital, Singapore.

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February 2018

Linkage between the bacterial acid stress and stringent responses: the structure of the inducible lysine decarboxylase.

EMBO J 2011 Mar 28;30(5):931-44. Epub 2011 Jan 28.

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

The Escherichia coli inducible lysine decarboxylase, LdcI/CadA, together with the inner-membrane lysine-cadaverine antiporter, CadB, provide cells with protection against mild acidic conditions (pH∼5). To gain a better understanding of the molecular processes underlying the acid stress response, the X-ray crystal structure of LdcI was determined. The structure revealed that the protein is an oligomer of five dimers that associate to form a decamer. Surprisingly, LdcI was found to co-crystallize with the stringent response effector molecule ppGpp, also known as the alarmone, with 10 ppGpp molecules in the decamer. ppGpp is known to mediate the stringent response, which occurs in response to nutrient deprivation. The alarmone strongly inhibited LdcI enzymatic activity. This inhibition is important for modulating the consumption of lysine in cells during acid stress under nutrient limiting conditions. Hence, our data provide direct evidence for a link between the bacterial acid stress and stringent responses.
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http://dx.doi.org/10.1038/emboj.2011.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049219PMC
March 2011

Structure of RavA MoxR AAA+ protein reveals the design principles of a molecular cage modulating the inducible lysine decarboxylase activity.

Proc Natl Acad Sci U S A 2010 Dec 9;107(52):22499-504. Epub 2010 Dec 9.

Department of Biochemistry, University of Toronto, Toronto, ON, Canada M5S 1A8.

The MoxR family of AAA+ ATPases is widespread throughout bacteria and archaea but remains poorly characterized. We recently found that the Escherichia coli MoxR protein, RavA (Regulatory ATPase variant A), tightly interacts with the inducible lysine decarboxylase, LdcI/CadA, to form a unique cage-like structure. Here, we present the X-ray structure of RavA and show that the αβα and all-α subdomains in the RavA AAA+ module are arranged as in magnesium chelatases rather than as in classical AAA+ proteins. RavA structure also contains a discontinuous triple-helical domain as well as a β-barrel-like domain forming a unique fold, which we termed the LARA domain. The LARA domain was found to mediate the interaction between RavA and LdcI. The RavA structure provides insights into how five RavA hexamers interact with two LdcI decamers to form the RavA-LdcI cage-like structure.
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http://dx.doi.org/10.1073/pnas.1009092107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012504PMC
December 2010

Sterigmatocystins from the deep-sea-derived fungus Aspergillus versicolor.

J Antibiot (Tokyo) 2011 Feb 1;64(2):193-6. Epub 2010 Dec 1.

Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, PR China.

Three new sterigmatocystin derivatives, oxisterigmatocystin A (1), oxisterigmatocystin B (2) and oxisterigmatocystin C (3), together with one known compound, 5-methoxysterigmatocystin (4), were isolated from the deep-sea-derived fungus Aspergillus versicolor. The structures of the new compounds were elucidated by spectroscopic methods. The cytotoxicities of compounds 1-4 were evaluated against the A-549 and HL-60 cell lines. Compound 4 exhibited moderate cytotoxicities against the A-549 and HL-60 cell lines with IC(50) value of 3.86 and 5.32 μM, respectively.
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http://dx.doi.org/10.1038/ja.2010.154DOI Listing
February 2011

Acid stress response in enteropathogenic gammaproteobacteria: an aptitude for survival.

Biochem Cell Biol 2010 Apr;88(2):301-14

Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.

Enteric bacteria such as Escherichia coli have acquired a wide array of acid stress response systems to counteract the extreme acidity encountered when invading the host's digestive or urinary tracts. These acid stress response systems are both enzyme and chaperone based. The 3 main enzyme-based acid resistance pathways are glutamate-, arginine-, and lysine-decarboxylase pathways. They are under a complex regulatory network allowing the bacteria to fine tune its response to the external environment. HdeA and HdeB are the main chaperones involved in acid stress response. The decarboxylase systems are also found in Vibrio cholera, Vibrio vulnifus, Shigella flexneri, and Salmonella typhimurium, although some differences exist in their functional mechanism and regulation.
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http://dx.doi.org/10.1139/o09-182DOI Listing
April 2010

Alkaloids from a deep ocean sediment-derived fungus Penicillium sp. and their antitumor activities.

J Antibiot (Tokyo) 2010 Apr 26;63(4):165-70. Epub 2010 Feb 26.

Key Laboratory of Marine Drugs, Chinese Ministry of Education School of Medicine and Pharmacy, Institute of Marine Drugs and Food, Ocean University of China, Qingdao, PR China.

Four new alkaloids, including two new meleagrin analogs, meleagrin D (1) and E (2), and two new diketopiperazines, roquefortine H (3) and I (4), were isolated from a deep ocean sediment-derived fungus Penicillium sp. Meleagrin D (1) and E (2) possess unprecedented acetate-mevalonate-derived side chains on the imidazole moiety. These new meleagrins showed weak cytotoxicity against the A-549 cell line, whereas meleagrin B (5) and meleagrin (6), which were isolated previously from the same strain, induced HL-60 cell apoptosis or arrested the cell cycle through G(2)/M phase, respectively. The results indicate that the distinct substitutions on the imidazole ring significantly influence the cytotoxicity of the meleagrin alkaloids.
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http://dx.doi.org/10.1038/ja.2010.11DOI Listing
April 2010

Carisbamate, a novel antiepileptic candidate compound, attenuates alcohol intake in alcohol-preferring rats.

Alcohol Clin Exp Res 2009 Aug 30;33(8):1366-73. Epub 2009 Apr 30.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA.

Background: Since 1994, when naltrexone (Revia) was approved by the FDA for the treatment of alcoholism, only 2 other drugs (Campral and Topamax have been approved for alcoholism treatment. However, various experimental drugs, including antiepileptic medications, have been tested in both animal models and in humans with some promising results. The purpose of this project was to study the effect of the novel neuromodulator carisbamate, which is in development for epilepsy treatment, on alcohol intake in selectively bred alcohol-preferring rats.

Methods: Male alcohol-preferring inbred P rats were allowed to freely drink water or alcohol (10%, v/v) using a 2-bottle choice procedure. After stable baselines for alcohol and water intakes were established, the acute effects of oral carisbamate (0, 10, 30, 45, 60, and 90 mg/kg) were assessed. Then, the chronic effect of the compound (60 mg/kg/day for 14 consecutive days) on alcohol intake was assessed in a separate group of male P rats. In another set of experiments, the effects of carisbamate and naltrexone on alcohol withdrawal-induced elevated drinking of alcohol, an index of craving, were compared. Rats were withdrawn from alcohol for 24 hours and were given vehicle, 20 mg/kg naltrexone or 60 mg/kg carisbamate 30 minutes before re-exposure to alcohol. Alcohol and water intake was measured 6 hours after alcohol re-exposure. To determine the effects of carisbamate on saccharin preference, rats were put on a 2-bottle choice of water versus a solution of 2% saccharin. Then, the effect of the highest dose of carisbamate (90 mg/kg) and naltrexone (20 mg/kg) and the vehicle on saccharin preference was determined.

Results: Our results showed that there was a selective dose-dependent reduction in alcohol intake and preference in the alcohol-preferring P rat after an acute oral administration of carisbamate. There were no significant effects on food or water intake. Chronic administration of carisbamate significantly reduced alcohol intake and preference initially, but partial tolerance developed after the 10th treatment. The degree of tolerance development was less than that observed for naltrexone. Acute administration of carisbamate was more effective than naltrexone in reducing enhanced alcohol intake after a period of alcohol deprivation. Compared with control vehicle neither carisbamate nor naltrexone had a significant effect on saccharin intake and preference.

Conclusion: The novel neuromodulator compound carisbamate has a favorable profile of effects on alcohol intake and related measures and should be considered for testing on human alcoholics.
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http://dx.doi.org/10.1111/j.1530-0277.2009.00966.xDOI Listing
August 2009

Cytotoxic sorbicillinoids and bisorbicillinoids from a marine-derived fungus Trichoderma sp.

Chem Pharm Bull (Tokyo) 2009 Feb;57(2):220-3

Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qindao, China.

Four sorbicillinoids (1-4) and seven bisorbicillinoids (5-11), including two new compounds, 6-demethylsorbicillin (1) and 10,11-dihydrobisvertinolone (6), were isolated from a marine-derived fungus Trichoderma sp. Their cytotoxic activities against HL-60 cell line were evaluated by Sulforhodamine B (SRB) assay method and flow cytometric analysis.
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http://dx.doi.org/10.1248/cpb.57.220DOI Listing
February 2009

Carisbamate, a novel neuromodulator, inhibits voltage-gated sodium channels and action potential firing of rat hippocampal neurons.

Epilepsy Res 2009 Jan 14;83(1):66-72. Epub 2008 Nov 14.

Analgesics Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Welsh & McKean Roads, P.O. Box 776, Spring House, PA 19477-0776, USA.

Carisbamate (RWJ-333369; (S)-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is a novel investigational antiepileptic drug that exhibits a broad-spectrum of activity in a number of animal models of seizure and drug refractory epilepsy. In an effort to understand the molecular mechanism by which carisbamate produces its antiepileptic actions, we studied its effects on the function of voltage-gated, rat brain sodium and potassium channels and on the repetitive firing of action potentials in cultured rat hippocampal neurons. In whole-cell patch clamp recording, carisbamate resulted in a concentration-, voltage- and use-dependent inhibition of rat Nav1.2, with an IC(50) value of 68 microM at -67 mV. In rat hippocampal neurons, carisbamate similarly blocked voltage-gated sodium channels, with an IC(50) value of 89 microM at -67 mV, and inhibited repetitive firing of action potentials in a concentration-dependent manner (by 46% at 30 microM and 87% at 100 microM, respectively). Carisbamate had no effect on the steady-state membrane potential or voltage-gated potassium channels (K(v)) in these neurons. These inhibitory effects of carisbamate occurred at therapeutically relevant concentrations in vivo, raising the possibility that block of voltage-gated sodium channels by carisbamate contributes to its antiepileptic activity.
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http://dx.doi.org/10.1016/j.eplepsyres.2008.09.006DOI Listing
January 2009

Basis for physician recommendations for adjuvant radioiodine therapy in early-stage thyroid carcinoma: principal findings of the Canadian-American thyroid cancer survey.

Endocr Pract 2008 Mar;14(2):175-84

Division of Endocrinology, Department of Medicine, University Health Network, Toronto, Ontario, Canada.

Objective: To explore physician recommendations regarding radioiodine remnant ablation (RRA) as adjuvant treatment in early-stage well-differentiated thyroid carcinoma (WDTC), their rationale for administration of RRA, and their willingness to involve patients' opinions in decision making about the use of RRA.

Methods: We surveyed a representative sample of specialty physicians in Canada and the United States and asked survey participants whether they would recommend adjuvant RRA after thyroidectomy for a 1.6-cm papillary thyroid carcinoma (Likert scale of agreement responses from 1 to 7; strong agreement >or=6). Factor analysis was performed to explore the rationale for recommendations. We asked whether physicians accepted the role of patients' preferences in decision making about administration of RRA, and backward conditional logistic regression analysis was used to identify predictors of strong acceptance.

Results: The effective response rate for the survey was 56.3% (486 of 864), with 62.8% (295 of 470 respondents) strongly recommending RRA. Strong RRA recommendations were founded in opinions that RRA (1) decreases WDTC-related mortality and recurrence and (2) facilitates WDTC follow-up at low risk of adverse effects. Approximately a third of the survey respondents (152 of 474) strongly agreed with incorporation of patients' preferences in decision making regarding the use of RRA. Physicians without firm convictions about the efficacy of RRA in decreasing disease-related outcomes and those practicing in the United States were most likely to indicate strong support for incorporating patients' preferences in decision making about RRA.

Conclusion: The recommendations of physicians regarding use of adjuvant RRA are founded in beliefs in intervention efficacy and follow-up practices. Physicians in medical practice in the United States and those without strong convictions about RRA efficacy are most likely to incorporate patients' views in individualizing decisions about RRA therapy.
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http://dx.doi.org/10.4158/EP.14.2.175DOI Listing
March 2008

Regional differences in opinions on adjuvant radioactive iodine treatment of thyroid carcinoma within Canada and the United States.

Thyroid 2007 Dec;17(12):1235-42

Division of Endocrinology and Department of Medicine, University Health Network Toronto, Ontario, Canada.

Objective: To identify regional differences in recommendations for radioactive iodine remnant ablation (RRA) in early stage well-differentiated thyroid carcinoma (WDTC) within Canada and the United States.

Design: A cross-sectional written survey of a sample of physicians in specialties potentially involved in thyroid cancer care was performed in 2006. Participants were asked if they recommended RRA for a hypothetical 38-year-old woman with a solitary, 1.6-cm papillary carcinoma resected by total thyroidectomy. Exploratory regional comparisons were performed using Student t tests or analysis of variance. The regions studied were western Canada, eastern Canada (Ontario, the Maritimes), Quebec, the northeastern United States, the western and midwestern United States, and the southern United States. In a secondary multivariable logistic regression analysis, we explored potential relationships between individual respondent characteristics RRA recommendations.

Main Outcome: Agreement with case-based RRA recommendations was measured on a Likert scale of 1 to 7 (7 = strongest agreement).

Results: The effective response rate was 56.3% (486/864). There were significant differences in RRA recommendations among the regions studied (F = 11.99, 5 df, p < 0.001); national boundaries did not explain regional variations. For the sample case, the strongest support for RRA was in Quebec and the southern United States, intermediate support in eastern Canada and the northeastern United States, and the least support in western Canada and the western and midwestern United States. Academic affiliation and surgical specialty were independently inversely associated with strong RRA recommendations.

Conclusions: There are significant regional differences in physician-based RRA recommendations in early stage WDTC within Canada and the United States. Physician specialty and practice characteristics may influence RRA recommendations.
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http://dx.doi.org/10.1089/thy.2007.0077DOI Listing
December 2007

The novel antiepileptic agent RWJ-333369-A, but not its analog RWJ-333369, reduces regional cerebral edema without affecting neurobehavioral outcome or cell death following experimental traumatic brain injury.

Restor Neurol Neurosci 2007 ;25(2):77-90

Traumatic Brain Injury Laboratory, Department of Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Purpose: To evaluate the therapeutic efficacy of two antiepileptic compounds, RWJ-333369 and RWJ-333369-A in a well-established experimental model of lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat.

Methods: Anethestized Male Sprague-Dawley rats (n=227) were subjected to lateral FP brain injury or sham-injury. Animals were randomized to receive treatment with RWJ-333369 (60 mg/kg, p.o.) or its analog RWJ-333369-A (60 mg/kg, p.o.), or vehicle (equal volume) at 15 minutes, 4, 8, and 24 hours post-injury. In Study I, animals were assessed at 48 hours for acute motor and cognitive function and then sacrificed to evaluate regional cerebral edema. In Study II, animals were evaluated post-injury for motor function at 48 hours and weekly thereafter from 1 to 4 weeks. Post-traumatic learning ability was assessed 4 weeks post-injury, followed by evaluation of hemispheric tissue loss.

Results: In Study I, no improvement in acute memory or motor function was observed following administration of either RWJ-333369 or RWJ-333369-A in brain-injured animals compared to vehicle-treated, brain-injured animals. However, brain-injured animals receiving treatment with RWJ-333369-A had a significant reduction in post-traumatic cerebral edema in both injured and contralateral hippocampus compared to brain-injured, vehicle-treated controls (p<0.05). In Study II, treatment with either compound did not result in any improvement of neuromotor function, learning ability or change in lesion volume following brain injury.

Conclusion: These results indicate that the novel antiepileptic compound RWJ-333369-A reduces post-traumatic hippocampal edema without affecting neurobehavioral or histological outcome. It remains unclear whether this small effect on hippocampal edema ie related to the ability of this compound to attenuate seizure activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2377455PMC
November 2007

The synthesis and evaluation of 10- and 12-membered ring benzofused enediyne amino acids.

Bioorg Med Chem 2005 Nov;13(21):5936-48

Drug Discovery Division, Johnson, & Johnson Pharmaceutical Research and Development, Spring House, PA 19477, USA.

The enediyne moiety is a versatile functional group found in natural anticancer and anti-infective agents, undergoing the Bergman cyclization reaction to afford a diradical which cleaves double-stranded DNA. We have incorporated the enediyne group into 10- (4-10) and 12-membered ring (11) cyclic amino acids and dipeptides, respectively, and explored their relative reactivity toward cyclization, varying N-substitution in the case of the 10-membered ring substrate, which gave the expected cyclization products in good yields when using either thermal conditions in the presence or absence of microwave irradiation. The N-tosyl substituted derivative (4) was shown to nick double-stranded supercoiled DNA. N-Arylsulfonyl substitution on the ring promoted the cyclization, when compared to N-mesyl or acyl substitution, possibly because of a pi-pi stacking effect as an endo-relationship of the aryl group with the enediyne was demonstrated in both the solid state and in solution. The 12-membered ring enediyne dipeptide (11) was inert to the Bergman cyclization under a variety of conditions. When this substrate was irradiated with ultraviolet light, regio- and stereospecific reduction was observed in which one of the alkynes was reduced to a Z-olefin (47).
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http://dx.doi.org/10.1016/j.bmc.2005.07.016DOI Listing
November 2005

A high-throughput monoamine oxidase inhibition assay using liquid chromatography with tandem mass spectrometry.

Rapid Commun Mass Spectrom 2004 ;18(8):834-40

Division of Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, LLC, Spring House, PA 19477-0779, USA.

A highly efficient method utilizing liquid chromatography with tandem mass spectrometry (LC/MS/MS) was developed and employed for high-throughput screening of compounds for monoamine oxidase (MAO) inhibition. The method used kynuramine as a common substrate for both MAO-A and MAO-B in incubations, and the 4-hydroxyquinoline (4-HQ) resulting from deamination of kynuramine followed by intramolecular condensation was analyzed using LC/MS/MS; formation of 4-HQ was used as the marker of MAO activity to evaluate the effects of test compounds. Isocratic liquid chromatography was applied to reduce the run time to 2 min. Because of the high specificity and sensitivity of detection of 4-HQ by LC/MS/MS, this method was able to use MAO enzymes at very low concentrations and to perform short incubations; as a result, consumable cost was minimized, and sample preparations were completely avoided. The inhibition data are highly reproducible, and the IC(50) values determined by the method are in good agreement with literature values. The results suggest that this method is very robust and can be used as a generic approach to screen for MAO inhibitors in drug discovery.
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http://dx.doi.org/10.1002/rcm.1415DOI Listing
May 2004

2,3-Diaryl-5-anilino[1,2,4]thiadiazoles as melanocortin MC4 receptor agonists and their effects on feeding behavior in rats.

Bioorg Med Chem 2003 Jan;11(2):185-92

Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Rds., PO Box 776, Spring House, PA 19477, USA.

The melanocortin-4 receptor (MC4) modulates physiological functions such as feeding behavior, nerve regeneration, and drug addiction. Using a high throughput screen based on (125)I-NDP-MSH binding to the human MC4 receptor, we discovered 2,3-diaryl-5-anilino[1,2,4]thiadiazoles 3 as potent and selective MC4 receptor agonists. Through SAR development on the three attached aryl rings, we improved the binding affinity from 174 nM to 4.4 nM IC(50). When delivered intraperitoneally, compounds 3a, 3b, and 3c induced significant inhibition of food intake in a fasting-induced feeding model in rats. When delivered orally, these compounds lost activity, mainly due to rapid metabolism to inactive imidoylthiourea reduction products.
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http://dx.doi.org/10.1016/s0968-0896(02)00428-5DOI Listing
January 2003
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