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  1. Article ; Online: Current tools for norovirus drug discovery.

    Weerasekara, Sahani / Prior, Allan M / Hua, Duy H

    Expert opinion on drug discovery

    2016  Volume 11, Issue 6, Page(s) 529–541

    Abstract: Introduction: Rapid transmission of norovirus often occurs due to its low infectious dosage, high genetic diversity and its short incubation time. The viruses cause acute gastroenteritis and may lead to death. Presently, no effective vaccine or ... ...

    Abstract Introduction: Rapid transmission of norovirus often occurs due to its low infectious dosage, high genetic diversity and its short incubation time. The viruses cause acute gastroenteritis and may lead to death. Presently, no effective vaccine or selective drugs accepted by the United States Food and Drug Administration (FDA) are available for the treatment of norovirus. Advances in the development of norovirus replicon cell lines, GII.4-Sydney HuNoV strain human B cells, and murine and gnotobiotic pig norovirus models have facilitated the discovery of effective small molecule inhibitors in vitro and in vivo.
    Areas covered: This review gives a brief discussion of the biology and replication of norovirus before highlighting the discovery of anti-norovirus molecules. The article coverage includes: an overview of the current state of norovirus drug discovery, the targeting of the norovirus life cycle, the inhibition of structural and nonstructural proteins of norovirus such as proteases and polymerase, and the blockage of virus entry into host cells. Finally, anti-norovirus drugs in the clinical development stage are described.
    Expert opinion: The current approach for the counteraction of norovirus focuses on the inhibition of viral RNA polymerase, norovirus 3C-like protease and the structural proteins VP1 as well as the blockade of norovirus entry. Broad-spectrum anti-norovirus molecules, based on the inhibition of 3C-like protease, have been developed. Other host factors and ways to overcome the development of resistance through mutation are also being examined. A dual approach in targeting viral and host factors may lead to an effective counteraction of norovirus infection. Current successes in developing norovirus replicon harboring cells and norovirus infected human cells, as well as murine norovirus models and other animal models such as piglets have facilitated the discovery of effective drugs and helped our understanding of its mechanism of action.
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; Caliciviridae Infections/drug therapy ; Caliciviridae Infections/transmission ; Caliciviridae Infections/virology ; Disease Models, Animal ; Drug Design ; Drug Discovery/methods ; Drug Resistance, Viral ; Gastroenteritis/drug therapy ; Gastroenteritis/virology ; Humans ; Norovirus/drug effects ; Norovirus/isolation & purification
    Chemical Substances Antiviral Agents
    Keywords covid19
    Language English
    Publishing date 2016-06
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2259618-5
    ISSN 1746-045X ; 1746-0441
    ISSN (online) 1746-045X
    ISSN 1746-0441
    DOI 10.1080/17460441.2016.1178231
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: SYNTHESIS OF 1,3,4-OXADIAZOLES AS SELECTIVE T-TYPE CALCIUM CHANNEL INHIBITORS.

    Zhang, Man / Zou, Bende / Gunaratna, Medha J / Weerasekara, Sahani / Tong, Zongbo / Nguyen, Thi D T / Koldas, Serkan / Cao, William S / Pascual, Conrado / Xie, Xinmin Simon / Hua, Duy H

    Heterocycles

    2019  Volume 101, Issue 1, Page(s) 145–164

    Abstract: Neuropathic pain, epilepsy, insomnia, and tremor disorder may arrive from an increase of intracellular ... ...

    Abstract Neuropathic pain, epilepsy, insomnia, and tremor disorder may arrive from an increase of intracellular Ca
    Language English
    Publishing date 2019-06-20
    Publishing country Japan
    Document type Journal Article
    ISSN 0385-5414
    ISSN 0385-5414
    DOI 10.3987/com-19-s(f)5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Comparison of strategies for enhancing RNA interference efficiency in Ostrinia nubilalis.

    Cooper, Anastasia Mw / Song, Huifang / Yu, Zhitao / Biondi, Marie / Bai, Jun / Shi, Xuekai / Ren, Zhaoyang / Weerasekara, Sahani M / Hua, Duy H / Silver, Kristopher / Zhang, Jianzhen / Zhu, Kun Yan

    Pest management science

    2020  Volume 77, Issue 2, Page(s) 635–645

    Abstract: Background: Targeting insect-specific genes through post-transcriptional gene silencing with RNA interference (RNAi) is a new strategy for insect pest management. However, lepidopterans are recalcitrant to RNAi, which prevents application of novel RNAi ... ...

    Abstract Background: Targeting insect-specific genes through post-transcriptional gene silencing with RNA interference (RNAi) is a new strategy for insect pest management. However, lepidopterans are recalcitrant to RNAi, which prevents application of novel RNAi technology to many notorious pests, including Ostrinia nubilalis (ECB). Strategies for enhancing RNAi efficiency, including large doses of double-stranded RNA (dsRNA), nuclease inhibitors, transfection reagents, and nanoparticles, have proved useful in other insects exhibiting substantial dsRNA degradation, a major mechanism limiting RNAi efficacy. To determine if similar strategies can enhance RNAi efficiency in ECB, various reagents were tested for their ability to enhance dsRNA stability in ECB tissues, then compared for their effectiveness in whole ECB.
    Results: Ex vivo incubation experiments revealed that Meta dsRNA lipoplexes, EDTA, chitosan-based dsRNA nanoparticles, and Zn
    Conclusion: These results indicate that enhancing dsRNA stability is insufficient to improve RNAi efficiency in ECB and suggests the existence of additional, complex mechanisms contributing to low RNAi efficiency in ECB.
    MeSH term(s) Animals ; Genes, Insect ; Hemolymph ; Moths ; RNA Interference ; RNA, Double-Stranded/genetics
    Chemical Substances RNA, Double-Stranded
    Language English
    Publishing date 2020-10-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2001705-4
    ISSN 1526-4998 ; 1526-498X
    ISSN (online) 1526-4998
    ISSN 1526-498X
    DOI 10.1002/ps.6114
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Synthesis of 1,4- and 1,4,4-substituted piperidines for the inhibition of neuronal T-type Ca2+ channels and mitigation of neuropathic pain in mice

    Medha J. Gunaratna / Duy H. Hua / Bende Zou / Conrado Pascual / William Cao / Man Zhang / Sahani Weerasekara / Thi D. T. Nguyen / Kui Xiao / Xinmin Simon Xie

    ARKIVOC, Vol 2019, Iss 3, Pp 22-

    2019  Volume 39

    Keywords Organic chemistry ; QD241-441
    Language English
    Publishing date 2019-01-01T00:00:00Z
    Publisher Arkat USA, Inc.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Correction: Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor.

    Kim, Yunjeong / Liu, Hongwei / Kankanamalage, Anushka C Galasiti / Weerasekara, Sahani / Hua, Duy H / Groutas, William C / Chang, Kyeong-Ok / Pedersen, Niels C

    PLoS pathogens

    2016  Volume 12, Issue 5, Page(s) e1005650

    Abstract: This corrects the article DOI: 10.1371/journal.ppat.1005531.]. ...

    Abstract [This corrects the article DOI: 10.1371/journal.ppat.1005531.].
    Keywords covid19
    Language English
    Publishing date 2016-05
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7366
    ISSN (online) 1553-7374
    ISSN 1553-7366
    DOI 10.1371/journal.ppat.1005650
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Comparison of strategies for enhancing RNA interference efficiency in Ostrinia nubilalis

    Cooper, Anastasia MW / Song, Huifang / Yu, Zhitao / Biondi, Marie / Bai, Jun / Shi, Xuekai / Ren, Zhaoyang / Weerasekara, Sahani M / Hua, Duy H / Silver, Kristopher / Zhang, Jianzhen / Zhu, Kun Yan

    Pest management science. 2021 Feb., v. 77, no. 2

    2021  

    Abstract: BACKGROUND: Targeting insect‐specific genes through post‐transcriptional gene silencing with RNA interference (RNAi) is a new strategy for insect pest management. However, lepidopterans are recalcitrant to RNAi, which prevents application of novel RNAi ... ...

    Abstract BACKGROUND: Targeting insect‐specific genes through post‐transcriptional gene silencing with RNA interference (RNAi) is a new strategy for insect pest management. However, lepidopterans are recalcitrant to RNAi, which prevents application of novel RNAi technology to many notorious pests, including Ostrinia nubilalis (ECB). Strategies for enhancing RNAi efficiency, including large doses of double‐stranded RNA (dsRNA), nuclease inhibitors, transfection reagents, and nanoparticles, have proved useful in other insects exhibiting substantial dsRNA degradation, a major mechanism limiting RNAi efficacy. To determine if similar strategies can enhance RNAi efficiency in ECB, various reagents were tested for their ability to enhance dsRNA stability in ECB tissues, then compared for their effectiveness in whole ECB. RESULTS: Ex vivo incubation experiments revealed that Meta dsRNA lipoplexes, EDTA, chitosan‐based dsRNA nanoparticles, and Zn²⁺ enhanced dsRNA stability in ECB hemolymph and gut content extracts, compared with uncoated dsRNA. Despite these positive results, the reagents used in this study were ineffective at enhancing RNAi efficiency in ECB in vivo. To reduce assay time and required dsRNA, midguts were dissected and incubated in tissue culture medium containing dsRNA with and without reagents. These experiments showed that RNAi efficiency varied between target genes, and nuclease inhibitors improved RNAi efficiency for only a portion of the refractory target genes investigated ex vivo. CONCLUSION: These results indicate that enhancing dsRNA stability is insufficient to improve RNAi efficiency in ECB and suggests the existence of additional, complex mechanisms contributing to low RNAi efficiency in ECB.
    Keywords Ostrinia nubilalis ; RNA interference ; culture media ; double-stranded RNA ; genes ; hemolymph ; insect control ; tissue culture ; transfection
    Language English
    Dates of publication 2021-02
    Size p. 635-645.
    Publishing place John Wiley & Sons, Ltd.
    Document type Article
    Note NAL-AP-2-clean ; JOURNAL ARTICLE
    ZDB-ID 2001705-4
    ISSN 1526-4998 ; 1526-498X
    ISSN (online) 1526-4998
    ISSN 1526-498X
    DOI 10.1002/ps.6114
    Database NAL-Catalogue (AGRICOLA)

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  7. Article ; Online: Chiral-Substituted Poly-N-vinylpyrrolidinones and Bimetallic Nanoclusters in Catalytic Asymmetric Oxidation Reactions.

    Hao, Bo / Gunaratna, Medha J / Zhang, Man / Weerasekara, Sahani / Seiwald, Sarah N / Nguyen, Vu T / Meier, Alex / Hua, Duy H

    Journal of the American Chemical Society

    2016  Volume 138, Issue 51, Page(s) 16839–16848

    Abstract: A new class of poly-N-vinylpyrrolidinones containing an asymmetric center at C5 of the pyrrolidinone ring were synthesized from l-amino acids. The polymers, particularly 17, were used to stabilize nanoclusters such as Pd/Au for the catalytic asymmetric ... ...

    Abstract A new class of poly-N-vinylpyrrolidinones containing an asymmetric center at C5 of the pyrrolidinone ring were synthesized from l-amino acids. The polymers, particularly 17, were used to stabilize nanoclusters such as Pd/Au for the catalytic asymmetric oxidations of 1,3- and 1,2-cycloalkanediols and alkenes, and Cu/Au was used for C-H oxidation of cycloalkanes. It was found that the bulkier the C5 substituent in the pyrrolidinone ring, the greater the optical yields produced. Both oxidative kinetic resolution of (±)-1,3- and 1,2-trans-cycloalkanediols and desymmetrization of meso cis-diols took place with 0.15 mol % Pd/Au (3:1)-17 under oxygen atmosphere in water to give excellent chemical and optical yields of (S)-hydroxy ketones. Various alkenes were oxidized with 0.5 mol % Pd/Au (3:1)-17 under 30 psi of oxygen in water to give the dihydroxylated products in >93% ee. Oxidation of (R)-limonene at 25 °C occurred at the C-1,2-cyclic alkene function yielding (1S,2R,4R)-dihydroxylimonene 49 in 92% yield. Importantly, cycloalkanes were oxidized with 1 mol % Cu/Au (3:1)-17 and 30% H
    MeSH term(s) Alkenes/chemistry ; Catalysis ; Metal Nanoparticles/chemistry ; Oxidation-Reduction ; Pyrrolidinones/chemistry ; Stereoisomerism
    Chemical Substances Alkenes ; Pyrrolidinones
    Language English
    Publishing date 2016-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/jacs.6b12113
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor.

    Kim, Yunjeong / Liu, Hongwei / Galasiti Kankanamalage, Anushka C / Weerasekara, Sahani / Hua, Duy H / Groutas, William C / Chang, Kyeong-Ok / Pedersen, Niels C

    PLoS pathogens

    2016  Volume 12, Issue 3, Page(s) e1005531

    Abstract: Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses ...

    Abstract Coronaviruses infect animals and humans causing a wide range of diseases. The diversity of coronaviruses in many mammalian species is contributed by relatively high mutation and recombination rates during replication. This dynamic nature of coronaviruses may facilitate cross-species transmission and shifts in tissue or cell tropism in a host, resulting in substantial change in virulence. Feline enteric coronavirus (FECV) causes inapparent or mild enteritis in cats, but a highly fatal disease, called feline infectious peritonitis (FIP), can arise through mutation of FECV to FIP virus (FIPV). The pathogenesis of FIP is intimately associated with immune responses and involves depletion of T cells, features shared by some other coronaviruses like Severe Acute Respiratory Syndrome Coronavirus. The increasing risks of highly virulent coronavirus infections in humans or animals call for effective antiviral drugs, but no such measures are yet available. Previously, we have reported the inhibitors that target 3C-like protease (3CLpro) with broad-spectrum activity against important human and animal coronaviruses. Here, we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP. Experimental FIP is 100% fatal once certain clinical and laboratory signs become apparent. We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated. Antiviral treatment was associated with a rapid improvement in fever, ascites, lymphopenia and gross signs of illness and cats returned to normal health within 20 days or less of treatment. Significant reduction in viral titers was also observed in cats. These results indicate that continuous virus replication is required for progression of immune-mediated inflammatory disease of FIP. These findings may provide important insights into devising therapeutic strategies and selection of antiviral compounds for further development for important coronaviruses in animals and humans.
    MeSH term(s) Animals ; Antiviral Agents/chemical synthesis ; Antiviral Agents/pharmacology ; Cat Diseases/drug therapy ; Cat Diseases/virology ; Cats ; Coronavirus Infections/drug therapy ; Coronavirus Infections/virology ; Coronavirus, Feline/drug effects ; Feline Infectious Peritonitis/drug therapy ; Feline Infectious Peritonitis/virology ; Female ; Male ; Protease Inhibitors/chemical synthesis ; Protease Inhibitors/pharmacology ; Virulence ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; Protease Inhibitors
    Keywords covid19
    Language English
    Publishing date 2016-03-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7366
    ISSN (online) 1553-7374
    ISSN 1553-7366
    DOI 10.1371/journal.ppat.1005531
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Correction

    Yunjeong Kim / Hongwei Liu / Anushka C Galasiti Kankanamalage / Sahani Weerasekara / Duy H Hua / William C Groutas / Kyeong-Ok Chang / Niels C Pedersen

    PLoS Pathogens, Vol 12, Iss 5, p e

    Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor.

    2016  Volume 1005650

    Abstract: This corrects the article DOI:10.1371/journal.ppat.1005531.]. ...

    Abstract [This corrects the article DOI:10.1371/journal.ppat.1005531.].
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2016-05-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: The Anti-Amyloid-β and Neuroprotective Properties of a Novel Tricyclic Pyrone Molecule.

    Maezawa, Izumi / Zou, Bende / Di Lucente, Jacopo / Cao, William S / Pascual, Conrado / Weerasekara, Sahani / Zhang, Man / Xie, Xinmin Simon / Hua, Duy H / Jin, Lee-Way

    Journal of Alzheimer's disease : JAD

    2017  Volume 58, Issue 2, Page(s) 559–574

    Abstract: There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug ... ...

    Abstract There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models. Here we report the selection and initial characterization of a new lead TP70, which exhibited an anti-Aβ therapeutic index even higher than CP2. Moreover, TP70 was able to reduce oxidative stress, inhibit acyl-coenzyme A:cholesterol acyltransferase (ACAT), and upregulate the expression of ATP-binding cassette subfamily A, member 1 (ABCA1), actions considered neuroprotective in AD. TP70 further showed excellent pharmacokinetic properties, including brain penetration and oral availability. When administered to 5xFAD mice via intraperitoneal or oral route, TP70 enhanced the overall solubility and decreased the level of cerebral Aβ, including both fibrillary and soluble Aβ species. Interestingly, TP70 enhanced N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potential (EPSP) in the hippocampal CA1 area, increased the magnitude of NMDA-dependent hippocampal long-term potentiation (LTP), a cellular model of learning and memory, and prevented the Aβ oligomer-impaired LTP. Significantly, a single dose of TP70 administered to aged 5xFAD mice was effective in mitigating the impaired LTP induction, recorded at 24 h after administration. Our results support a potential of TP70 in clinical development for AD in view of its synergistic neuroprotective actions, ability to positively modulate NMDA receptor-mediated hippocampal plasticity, and favorable pharmacokinetic properties in rodents.
    MeSH term(s) Alzheimer Disease/drug therapy ; Alzheimer Disease/pathology ; Alzheimer Disease/physiopathology ; Amyloid beta-Protein Precursor/genetics ; Amyloidogenic Proteins/metabolism ; Amyloidogenic Proteins/toxicity ; Animals ; Brain/drug effects ; Brain/metabolism ; Brain/pathology ; Cell Line, Tumor ; Disease Models, Animal ; Drinking Behavior/drug effects ; Excitatory Postsynaptic Potentials/drug effects ; Excitatory Postsynaptic Potentials/genetics ; Humans ; Locomotion/drug effects ; Locomotion/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Activity/genetics ; Mutation/genetics ; Neuroblastoma/pathology ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/therapeutic use ; Presenilin-1/genetics ; Pyrones/chemical synthesis ; Pyrones/chemistry ; Pyrones/therapeutic use
    Chemical Substances Amyloid beta-Protein Precursor ; Amyloidogenic Proteins ; Neuroprotective Agents ; PSEN1 protein, human ; Presenilin-1 ; Pyrones ; tricyclic pyrones
    Language English
    Publishing date 2017-04-28
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-161175
    Database MEDical Literature Analysis and Retrieval System OnLINE

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