Developing Myxovirus Inhibitors with Expanded Pathogen Target Range

Georgia State University, Atlanta GA

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Abstract

Paramyxoviruses are responsible for significant morbidity and mortality worldwide. Measles virus (MV), a member of the paramyxovirus family, accounts for approximately 600,000 deaths annually and is among the ten most lethal human pathogens. The virus is endemic in Africa, Asia and parts of Europe, and subject to frequent importation to the US. A herd immunity of approximately 95% is required to suppress periodic outbreaks. Despite high vaccination coverage in the US, cases are reported annually. No therapy is available for management of severe cases or rapid control of local outbreaks. It is therefore the long-term objective of this project to develop applicable antivirals that inhibit MV. Towards this goal a new class of small molecule MV fusion inhibitors has been identified that show strong promise as drug candidates. We propose structure-based design, pharmacophore extraction, quantitative structure-activity relationship (QSAR)-direeled optimization and efficacy testing to develop this compound class to a therapeutic lead. To maximize the prospect of success and counteract viral resistance that may emerge in the field, additional, structurally unrelated drug candidates will be identified in parallel. The first specific aim is therefore to biochemically assess the target site of the fusion inhibitors and develop a three- dimensional structure-based pharmacophore. Covalent photoaffinity labeling of the target protein by radiolabeled inhibitor analogs will be combined with protein microsequencing to define the physical binding site. The second specific aim identifies new hits through two complementary approaches: structure-guided database mining of available chemicals and high throughput screening using fluorescent MV as reporter. The third specific aim develops the fusion inhibitors and selected new hits to therapeutic leads through iterative rounds of QSAR-guided chemical modification and biotesting. Prior to lead development, new hits will be mechanistically characterized. The fourth specific aim is to assess the activity of selected leads against a representative panel of primary MV isolates that are frequently imported into the US and evaluate the efficacy of identified drug candidates in vivo using the cotton rat small animal model. Characteristic viral escape patterns will be identified for efficacious compounds that warrant future clinical development, and cross-resistance between structurally distinct therapeutic leads will be assessed. PERFORMANCE SITE(S) (organization, city, state) Emory University, Atlanta, GA Ohio State University, Columbus, OH PHS 398 (Rev. 09/04) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): Plemper, Richard Karl KEY PERSONNEL. See instructions. Use continuation pages as needed \o provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Plemper, Richard Karl rplempe Emory University PI Liotta, Dennis C Emory University Co-Pi Niewiesk, Stefan niewieskQ.1 Ohio State University Sub-Contractor Snyder, James P Emory University Co-Pi OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells [X] No LjYes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell llne(s) from the following list: http://StemcellS.nih.qov/reqiStrv/index.aSP. Use continuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line Disclosure Permission Statement. Applicable to SBIR/STTR Only. See SBIR/STTR instructions. Yes No PHS 398 (Rev. 09/04) Page 3 Form Page 2-contlnued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): Plemper, Richard Karl The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description, Performance Sites, Key Personnel, Other Significant Contributors, and Human Embryonic Stem Cells 2-3 Table of Contents Detailed Budget for Initial Budget Period (or Modular Budget) Budget for Entire Proposed Period of Support (not applicable with Modular Budget) Budgets Pertaining to Consortium/Contractual Arrangements (not applicable with Modular Budget) Biographical Sketch - Principal Investigator/Program Director (Not to exceed four pages) 6-8 Other Biographical Sketches (Not to exceed four pages for each - Seeinstructions) 9-19 Resources 20-21 Research Plan. IntroductiontoRevisedApplication(Nottoexceed3pages;SBIFl/STTRPhaseInottoexceed1page.) Introduction to Supplemental Application (Notto exceed one page) A. Specific Aims 22 B. Background and Significance 23-25 C. Preliminary Studies/Progress Report/ ^_ (Items A-D: not to exceed 25 pages*) 25-29 Phase I Progress Report (SBIR/STTR Phase II ONLY) | * SBIR/STTR Phase I: Items A-D limited to 15 pages. 29-46 D. Research Design and Methods E. Human Subjects Research 47 Protection of Human Subjects (Required if Item 4 on the Face Page is marked Yes) Data and Safety Monitoring Plan (Required if Item 4 on the Face Page is marked Yes and a Phase I, II, or III clinical trial is proposed) Inclusion of Women and Minorities (Required if Item 4 on the Face Page is marked Yes and is Clinical Research) Targeted/Planned Enrollment Table (for new and continuing clinical research studies) Inclusion of Children (Required if Item 4 on the Face Page is marked Yes) F. Vertebrate Animals 47 G. Literature Cited 48-54 H. Consortium/Contractual Arrangements 54-55 I. Resource Sharing 56 J. Letters of Support (e.g., Consultants) 56-58 Commercialization Plan (SBIR/STTR Phase II and Fast-Track ONLY) Checklist 59 Check if Appendix (Five collated sets. No page numbering necessary for Appendix.) Appendix is Included Appendices NOT PERMITTED for Phase I SBIR/STTR unless specifically solicited Number of publications and manuscripts accepted for publication (not to exceed 10) Other items (list): PHS 398 (Rev. 09/04) Form Page 3