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The Role of Cell Surface Heparan Sulfate in Enterovirus A71 Infections and the Development of Antiviral Agents Targeting Viral A

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The Role of Cell Surface Heparan Sulfate in Enterovirus A71 Infections and the Development of Antiviral Agents Targeting Viral A THE ROLE OF CELL SURFACE HEPARAN SULFATE IN ENTEROVIRUS A71 INFECTIONS AND THE DEVELOPMENT OF ANTIVIRAL AGENTS TARGETING VIRAL ATTACHMENT AND RNA TRANSLATION INITIATION TAN CHEE WAH THESIS SUBMITTED IN FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY FACULTY OF MEDICINE UNIVERSITY OF MALAYA KUALA LUMPUR 2014 UNIVERSITI MALAYA ORIGINAL LITERARY WORK DECLARATION Name of candidate: Tan Chee Wah (I.C/Passport No: 860902-56-5845) Registration/Matric No: MHA110001 Name of Degree: Doctor of Philosophy Title of Project Paper/Research Report/Dissertation/Thesis (“this Work”): The role of cell surface heparan sulfate in enterovirus A71 infections and the development of antiviral agents targeting viral attachment and RNA translation initiation Field of Study: Molecular Virology I do solemnly and sincerely declare that: (1) I am the sole author/writer of this Work; (2) This Work is original; (3) Any use of any work in which copyright exists was done by way of fair dealing and for permitted purposes and any excerpt or extract from, or reference to or reproduction of any copyright work has been disclosed expressly and sufficiently and the title of the Work and its authorship have been acknowledged in this Work; (4) I do not have any actual knowledge nor do I ought reasonably to know that the making of this work constitutes an infringement of any copyright work; (5) I hereby assign all and every rights in the copyright to this Work to the University of Malaya (“UM”), who henceforth shall be owner of the copyright in this Work and that any reproduction or use in any form or by any means whatsoever is prohibited without the written consent of UM having been first had and obtained; (6) I am fully aware that if in the course of making this Work I have infringed any copyright whether intentionally or otherwise, I may be subject to legal action or any other action as may be determined by UM. Candidate’s signature Date Subscribed and solemnly declared before, Witness’s Signature Date Name: Designation: ii ABSTRACT Enterovirus A71 (EV-A71) is the main causative agent of hand, foot and mouth disease (HFMD). Recent EV-A71 outbreaks in Asia-Pacific were not limited to mild HFMD, but were associated with neurological complications including aseptic meningitis, brainstem encephalitis and deaths. The absence of licensed therapeutics for clinical use has intensified research into anti-EV-A71 development. Since virus-host receptor interaction is the first essential event during virus infection, inhibitors that block this event could act as potential therapeutics. EV-A71 VP1 capsid protein is involved in viral-host receptor interactions and carries multiple receptor binding sites. Screening of 95 overlapping peptides covering the entire EV-A71 VP1 capsid protein was hypothesized to identify potential viral attachment inhibitors, as well as unknown receptors. Out of 95 overlapping peptides, a peptide designated as SP40 peptide significantly inhibited EV-A71-induced cytopathic effect, plaque formation, RNA synthesis and viral protein synthesis. Mechanism of action analysis revealed that SP40 peptide is not virucidal, but blocked EV-A71 attachment to the cell surface. Alanine scanning analysis showed that positively charged amino acids were critical for the antiviral activities. Sequence analysis revealed that SP40 peptide carried a heparan sulfate-specific binding domain (-RRKV-), which led to the hypothesis that EV-A71 could use cell surface heparan sulfate as an attachment receptor. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited EV-A71 infections in a dose- dependent manner. Interference with heparan sulfate biosynthesis either by sodium chlorate treatment or through transient knockdown of N-deacetylase/N-sulfotransferase- 1 and exostosin-1 expression reduced EV-A71 infection. Enzymatic removal of cell surface heparan sulfate by heparinase I/II/III inhibited EV-A71 infection. Biochemistry analysis revealed that EV-A71 interacts with heparan sulfate through electrostatic interactions. These findings support the hypothesis and confirmed that EV-A71 uses iii cell surface heparan sulfate as an attachment receptor. Other than the attachment inhibitor, this study also tested DNA-like antisense-mediated morpholino oligomers as anti-EV-A71 agents. Two octaguanidinium-conjugated morpholino oligomers (vivo- MOs) targeting EV-A71 internal ribosome entry site (IRES) significantly inhibited EV- A71 infections at multiple time points, in a dose-dependent manner. EV-A71 resistance to vivo-MO-1 arose after 8 blind passages in the presence of increased concentrations of vivo-MO-1, but not vivo-MO-2. A single nucleotide mutation at the extreme 3’ end (T to C substitution at position 533) was sufficient to confer vivo-MO-1 resistance. In mismatch tolerance analysis, results demonstrated that the positions and the number of mismatches affect vivo-MO-1 efficacy. A single mismatch at the center of the targeted region was more tolerable compared to a mismatch at the end of the targeted region. In conclusion, this study has identified an antiviral peptide that potentially blocks viral attachment to heparan sulfate, and led to the discovery of a novel EV-A71 attachment receptor. This study also identified two antisense-mediated vivo-MOs targeted sites for antiviral intervention. This study suggests that blocking of viral attachment and viral RNA translation are good strategies for antiviral intervention. iv ABSTRAK Enterovirus A71 (EV-A71) adalah agen utama penyebab penyakit kaki, tangan dan mulut (HFMD). Tanda-tanda klinikal HFMD adalah demam, ruam di tapak tangan dan kaki dan juga ulser di dalam mulut. Walau bagaimanapun, wabak EV-A71 di Asia Pasifik tidak terhad kepada HFMD yang ringan, tetapi dihubungkait dengan komplikasi neurologi seperti meningitis aseptik, ensefalitis, paralisis dan kematian. Pilihan rawatan untuk jangkitan EV-A71 adalah terhad kepada melegakan gejala jangkitan dan tiada agen antivirus yang berkesan untuk penggunaan klinikal. Oleh itu, pembangunan agen antivirus yang berkesan terhadap jangkitan EV-A71 adalah amat diperlukan dengan segera. Protein kapsid EV-A71 VP1 merupakan tapak pengikatan reseptor. Pemeriksaan 95 peptida bertindih meliputi seluruh EV-A71 VP1 protein kapsid dapat mengenalpasti inhibitor reseptor penyikat yang berpotensi serta mengenalpasti reseptor yang tidak diketahui. Daripada 95 peptida bertindih, peptida bernama SP40, didapati menghalang EV-A71 jangkitan dalam bentuk kesan sitopati (CPE), pembentukan plak, sintesis RNA dan sintesis protein di dalam kultur tisu. Analisis mekanisme tindakan membuktikan bahawa SP40 tidak menyahaktif virus, tetapi menyekat pengikatan reseptor EV-A71. Imbasan alanine mendedahkan bahawa asid amino yang bercas positif adalah penting untuk aktiviti-aktiviti antiviral. Analisis urutan peptida mendedahkan bahawa SP40 mempunyai domain pengikatan heparan sulfat (-RRKV-) yang spesifik. Ini telah menuju hipotesis penyelidikan bahawa EV-A71 menggunakan heparan sulfat sebagai tapak pengikatan reseptor. Heparin, dextran sulfat dan suramin didapati menghalang jangkitan EV-A71 dengan ketara. Dengan menggunakan varian heparin yang kekurangan kumpulan O-sulfat atau kedua-dua kumpulan O-sulfat and N-sulfat serta natrium klorat, kajian ini telah mengenalpastikan bahawa kumpulan sulfat dalam heparin adalah kritikal untuk kesan antivirus. Penyingkiran sel permukaan heparan sulfat dengan enzim heparinase atau halangan biosistensis heparan sulfat dengan siRNA v telah mengurangkan jangkitan EV-A71 dengan ketara. Analisis biokimia mendedahkan bahawa EV-A71berinteraksi dengan heparan sulfat melalui interaksi elektrostatik. Selain daripada inhibitor adhesi, kajian ini telah mengenal pasti dua perantara-antierti morpholino oligonukleotida berkonjugasi dengan octaguanidinium dendrimer (vivo-MO) yang menyasarkan tapak kemasukan internal ribosom (IRES) mempunyai aktiviti antivirus yang berkesan terhadap jangkitan EV-A71. Penyelidikan masa rawatan telah mengenalpastikan bahawa vivo-MO mengekalkan aktiviti-aktiviti antivirus apabila rawatan diberikan 4 jam sebelum atau 6 jam selepas jangkitan EV-A71. EV-A71 yang mempunyai rintangan terhadap vivo-MO-1 didapati mempunyai mutasi daripada T kepada C, dalam kedudukan 533 selepas lapan kali sub-kultur. Dengan menggunakan mutasi berarahan-tapak spesifik untuk analisi toleransi sepadan, kajian ini telah mengenalpastikan bahawa kedudukan mutasi dan juga bilangan mutasi adalah penting untuk aktiviti-aktiviti antivirus oleh vivo-MO. Mutasi di tengah-tengah rantau yang disasarkan adalah lebih ditoleransi berbanding dengan mutasi di hujung rantau yang disasarkan. Dalam kajian ini, saya telah mengenalpasti peptida antivirus yang berpotensi menyekat EV-A71 adhesi kepada heparan sulfat dan telah membawa kepada penemuan peranan heparan sulfat sebagai reseptor adhesi untuk EV-A71. Kajian ini juga mengenalpasti dua perantara-antierti vivo-MO tapak sasaran untuk pembangunan antivirus yang berkesan. vi ACKNOWLEDGEMENTS I would like to express my sincere thanks and utmost gratitude to: GOD for HIS limitless guidance, love, spiritual courage and strength to face the challenges and overcome the obstacles. Amen. Dr. Chan Yoke Fun for her unwavering guidance, sound advice and most importantly, for her support and the opportunity to continue my postgraduate studies under her close supervision in University of Malaya. I am indebted to you for providing me with the motivation to develop a passion towards science and sharing your research experiences with me.
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