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    Dengue Virus NS2B/NS3 Protease Inhibitors Exploiting the Prime Side

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    Authors
    Lin, Kuan-Hung
    Ali, Akbar
    Rusere, Linah
    Soumana, Djade I.
    Yilmaz, Nese Kurt
    Schiffer, Celia A.
    UMass Chan Affiliations
    Schiffer Lab
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2017-04-28
    Keywords
    Zika
    antimicrobial peptides
    antiviral agents
    dengue fever
    drug design
    protease inhibitors
    receptor-ligand interaction
    structural biology
    substrate
    Biochemistry
    Enzymes and Coenzymes
    Medicinal and Pharmaceutical Chemistry
    Medicinal-Pharmaceutical Chemistry
    Structural Biology
    Virology
    Virus Diseases
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    Abstract
    The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a small protein with high affinity for DENV protease. In this study, we designed a series of cyclic peptides interacting with both sides of the active site as inhibitors of dengue virus protease. The design was based on two aprotinin loops and aimed to leverage both key specific interactions of substrate sequences and the entropic advantage driving aprotinin's high affinity. By optimizing the cyclization linker, length, and amino acid sequence, the tightest cyclic peptide achieved a Ki value of 2.9 muM against DENV3 wild-type (WT) protease. These inhibitors provide proof of concept that both sides of DENV protease active site can be exploited to potentially achieve specificity and lower hydrophilicity in the design of inhibitors targeting DENV. IMPORTANCE: Viruses of the flaviviral family, including DENV and Zika virus transmitted by Aedes aegypti, continue to be a threat to global health by causing major outbreaks in tropical and subtropical regions, with no available direct-acting antivirals for treatment. A better understanding of the molecular requirements for the design of potent and specific inhibitors against flaviviral proteins will contribute to the development of targeted therapies for infections by these viruses. The cyclic peptides reported here as DENV protease inhibitors provide novel scaffolds that enable exploiting the prime side of the protease active site, with the aim of achieving better specificity and lower hydrophilicity than those of current scaffolds in the design of antiflaviviral inhibitors.
    Source
    J Virol. 2017 Apr 28;91(10). pii: e00045-17. doi: 10.1128/JVI.00045-17. Print 2017 May 15. Link to article on publisher's site
    DOI
    10.1128/JVI.00045-17
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/29110
    PubMed ID
    28298600
    Related Resources

    Link to Article in PubMed

    Rights
    Publisher PDF posted as allowed by the publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
    ae974a485f413a2113503eed53cd6c53
    10.1128/JVI.00045-17
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    UMass Chan Faculty and Researcher Publications
    Schiffer Lab Publications

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