Full Text AI-94-017 MOLECULAR AND STRUCTURAL APPROACHES TO ANTIVIRAL DRUG DESIGN NIH GUIDE, Volume 23, Number 19, May 20, 1994 RFA: AI-94-017 P.T. 34 Keywords: Antivirals Genetics Biology, Molecular Drug Design National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: June 22, 1994 Application Receipt Date: August 10, 1994 PURPOSE Therapeutic and prophylactic agents (other than vaccines) for viral infections that specifically inhibit virus replicative functions without interfering with host cell processes are likely to provide clinical benefit with minimal toxicity. The National Institute of Allergy and Infectious Diseases (NIAID) invites applications for novel research that applies an understanding of the genetics, structural biology, and molecular biology of virus replication and pathogenesis to the development of antiviral agents that are targeted to virus-specific or virus-induced functions. Research on any virus that is a human pathogen or that serves as a model for a human pathogen, except for human immunodeficiency virus (HIV) and/or other retroviruses, is an appropriate subject for an application. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Molecular and Structural Approaches to Antiviral Drug Design, is related to the priority area of therapy for viral diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Applications from minority investigators and women are encouraged. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the Cooperative Agreement (U01), an assistance mechanism, rather than an acquisition mechanism, in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of a study funded under cooperative agreement(s) are discussed later in this document under the section Terms and Conditions of Award. The total project period for applications submitted in response to this RFA may not exceed five years. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. This is a one-time RFA. At this time there are no plans to recompete this RFA. If the NIAID does not continue the program, awardees may submit grant applications through the usual investigator-initiated grants program. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for awards under this RFA will be $2,600,000. The NIAID anticipates making nine to twelve new and/or competing awards as a result of this request. If appropriate, collaboration with other investigators or institutions is encouraged. It is expected that the initial year's awards for successful applications will average $150,000 in direct costs. However, individual awards may be higher or lower. The earliest possible award date is July 1, 1995. RESEARCH OBJECTIVES Background Information The Division of Microbiology and Infectious Diseases (DMID) of the National Institute of Allergy and Infectious Disease (NIAID) invites applications for Cooperative Agreements to support research projects to develop molecularly targeted agents as inhibitors of virus infection. Viral diseases account for significant morbidity and mortality, as well as economic loss, worldwide. The DMID has targeted the control of infections caused by cytomegalovirus and other herpesviruses, papillomaviruses, hepatitis viruses, the respiratory viruses and "emerging viruses" as high priorities. (The Division of AIDS has responsibility for the control of HIV and other retroviral infections.) The DMID sponsors programs for both in vitro and animal model preclinical evaluation, as well as clinical trials, of promising experimental therapies. Since there is a critical public health need for effective, nontoxic agents for antiviral therapy, the NIAID would like to stimulate research on the design and discovery of novel antiviral agents. The search for effective therapeutic agents to combat these serious infectious diseases was long delayed by the widely-held belief that the intracellular nature of virus replication made the development of clinically useful drugs improbable. Indeed, because viruses subvert many host cellular metabolic processes to their own ends, the design of a selective antiviral therapy, i.e., one that inhibits the virus without harming the host, is a daunting challenge. This requirement for selectivity also makes it unlikely that agents with broad spectrum activity will be acceptably safe. Although most currently approved antiviral agents were discovered by random screening, most of these have significant associated toxicities and it is unlikely that the required specificity for safe antiviral agents will be discovered by chance. More recently, as knowledge of the molecular mechanisms of virus replication and pathogenesis has become available, it is evident that there are both virus-coded and virus-induced functions that may be specifically, or at least selectively, inhibited. The efficacy of acyclovir at inhibition of herpes simplex infection is a dramatic example and has resulted in significant industrial support for the development of derivatives of acyclovir and other nucleosides. Accordingly, targeted structural and genetic research offers the best hope for the discovery and development of safe and clinically effective antiviral therapies. The detailed understanding of the mechanisms of virus replication and the three dimensional structure of virions and virus proteins that is rapidly accumulating should be exploited to investigate additional innovative approaches to the design of molecularly targeted antivirals. Infectious processes that may provide vulnerable targets include virus attachment and entry, the synthesis and processing of nucleic acids and proteins, transport of macromolecules, assembly of progeny virions, the identification of viral markers on infected cells and the spread of virus to uninfected cells. It may also be possible to target latently infected cells. Other eligible targets include cellular functions involved in viral pathogenesis or protection from viral disease. This approach has been enthusiastically supported by AIDS research programs for several years, with the result that several agents are now in clinical trial (protease and tat inhibitors) and many more are in the early stages of development. However, comparable support has not been available for the many other viral infections which are serious clinical problems. The cooperative agreement mechanism is appropriate for this program since it fosters synergistic interactions among the multidisciplinary investigators whose efforts are all necessary for successful antiviral design and development. DMID maintains antiviral evaluation facilities which may, if appropriate, be made available awardees under this RFA. These facilities have the capability to evaluate compounds in vitro for activity against panels of herpesviruses (HSV-1, HSV-2, CMV, VZV, and EBV), respiratory viruses (influenza A, influenza B, parainfluenza, respiratory syncytial virus, adenovirus and measles), HPV and hepatitis B. Compounds are also evaluated for toxicity for stationary and exponentially growing primary human fibroblasts and for activity against multiple strains of each virus which include recent clinical isolates and drug-resistant strains. With the exception of EBV, DMID also supports animal models for the above-listed viruses. For example, the awardee may devise an agent that inhibits the expression of cloned respiratory syncytial virus or hepatitis B virus genes in vitro. The NIAID Scientific Coordinator can arrange for the agent to receive more extensive in vitro testing as well as evaluation in a cotton rat animal model for RSV infections or a woodchuck model for hepatitis B infection. This past year, agents developed by one current awardee have been tested as an aerosol-delivered therapy for a respiratory virus. For agents such as EBV and the bunyaviruses, the Scientific Coordinator may be able to facilitate testing by other government laboratories that do have these facilities. In addition, the awardee may want NIAID to assist in the eventual clinical testing of the agent. Alternatively, the awardee may pursue testing of his/her agent independently. Research Goals and Scope The purpose of this RFA is to stimulate research in the development of novel molecularly targeted approaches to antiviral therapy. This includes strategies for both the design of novel specific agents and development of methods for selective drug delivery. The strategies proposed should involve a molecular rationale for anticipated antiviral activity without significant concomitant cellular and/or organism toxicity. These include, but are not limited to, the use of three dimensional structural knowledge for inhibitor design, receptor interference, substrate analogues for viral enzymes, antisense and ribozyme oligonucleotides, immune-based approaches such as bifunctional antibodies and T-cell reconstitution, peptides, peptidomimetics and rationally-based drug combinations. Targeted approaches to drug delivery are also encouraged since drug toxicity often results from effects on uninfected tissues. Collaborations between different scientific disciplines, such as chemistry and virology, as well as collaborations between industrial and academic investigators are encouraged. Virus systems may be any (except HIV and related lentiviruses) that provide a model for a clinically important human viral infection. Possible choices include, but are not limited to, hepatitis B, C, and D virus, papillomavirus, cytomegalovirus, herpes simplex virus, varicella zoster virus, influenza viruses, respiratory syncytial virus, parainfluenza, coxsackievirus, dengue, arenaviruses, bunyaviruses, and rhinovirus. It is possible that research applications will involve the use of clinical specimens. If so, the issues discussed below in the section STUDY POPULATIONS should be addressed regarding the populations from which the specimens are obtained. Applications to conduct clinical trials are not responsive to this RFA and will be returned to the applicant. Terms and Conditions of Award: Awardee Rights and Responsibilities; Nature of Participation of NIAID Staff The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator, as well as the institutional official, at the time of award. These special Terms of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grants Administration Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grants Administration policy statements. I. Awardee Rights and Responsibilities a. The Principal Investigator defines the details for the project within the guidelines of the RFA, retains primary responsibility for the performance of the scientific activity, and agrees to accept close assistance of NIAID staff in aspects of scientific and technical management of the project in accordance with the terms mutually agreed upon prior to the award. b. The awardee is to plan and conduct the research stipulated in the application and to ensure that the results obtained are analyzed and published in a timely manner. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. c. The awardee is to participate in an annual meeting of investigators funded under this RFA to discuss progress and strategies for future research. II. NIAID Rights and Responsibilities Assistance via Cooperative Agreement differs from the traditional research grant in that, in addition to the normal programmatic and administrative stewardship responsibilities, the component awarding the Cooperative Agreement anticipates substantial programmatic involvement during performance of the project. NIAID staff assistance is to participate in, but not direct, the research to ensure that important disease targets are addressed. The Chief, Antiviral Research Branch, DMID will serve as Scientific Coordinator and will participate as a member of the research team. The Scientific Coordinator will interact with the Principal Investigators and Co-investigators in the overall research planning and in data analysis. During performance of the award, the NIAID Scientific Coordinator may provide appropriate assistance by participating in the design of research group activities; advising in the selection of sources or resources; coordinating or participating in collection and/or analysis of data; and, advising in management and technical performance. The Scientific Coordinator may assist with arrangements for the further evaluation, both in vitro and in animal models, of agents resulting from this research. However, the role of NIAID will be to facilitate and not to direct the activities. Specifically, it is presently envisioned that the NIAID will be actively engaged in the facilitation of components including assisting the awardees in: a. Collaborative participation in overall research planning and data analysis. Specifically, the NIAID Scientific Coordinator may suggest studies within the scope of the award's objectives and research activities; may present to the investigators experimental findings from published sources or from contract projects in support of these suggestions; may participate in the design of experiments; and may participate in the analysis of results. b. Provision of needed resources and information that may not be otherwise available to the investigator. This may include the provision of data from testing conducted in resource contract laboratories subject to the terms of confidentiality agreements with drug sponsors. c. In the event that an awardee's research results in a procedure or a product that requires testing of a nature beyond the awardee's capabilities, the NIAID Scientific Coordinator may provide resources available to the Institute for comprehensive preclinical efficacy evaluations. d. The NIAID Scientific Coordinator will organize an annual symposium in Bethesda, Maryland at which the principal investigators will discuss their progress. This will facilitate overall program planning and development, the evaluation of the feasibility of the attempted approaches, and will promote productive interactions among the successful applicants. The NIAID Scientific Coordinator will also ensure the participation in this symposium of investigators from other NIAID preclinical and clinical programs to provide the most relevant antiviral expertise possible to facilitate planning for future research and expedite the design and development of novel antiviral agents. III. Arbitration It is anticipated that decisions in activities outlined above as well as changes in research direction will be reached by consensus of the Principal Investigator and the NIAID Scientific Coordinator. Such changes may be occasioned by the emerging clinical importance of different infections or the suitability of developed approaches for the design of antiviral therapies for other infections. The manner of reaching this consensus and the decision-making authority will rest with the Principal Investigator. However, if a dispute should arise, the decision of a three member arbitration team will be binding. One member of this team will be chosen by the Principal Investigator and the second will be chosen by the NIAID Scientific Coordinator. These two members of the arbitration team will select the third member. STUDY POPULATIONS INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 9, 1994 (FR 59 11146-11151), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. NOTE: Peer review groups need adequate information about the composition of proposed study populations in all applications involving human subjects. To avoid delays in review of such applications, the NIAID therefore requires that, as a minimum, the application must contain demographic data about the clinic and/or in-patient population from which study subjects will be drawn: average hospital admissions per year; percentage distribution of black/hispanic/other minority/non-minority populations; gender; etc. Studies using non-hospital populations, such as community-based studies, should provide similar data about populations in the area or region from which the study subjects will be drawn. In the absence of current data, historical demographic information and/or previous recruitment data for similar studies from the proposed sites should be provided. LETTER OF INTENT Prospective applicants are asked to submit, by June 22, 1994 a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, the number and title of this RFA, and a list of the key investigators and their institution(s). Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Olivia Preble at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on the standard research grant application form PHS 398 (rev. 9/91). For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number and the words "MOLECULAR AND STRUCTURAL APPROACHES TO ANTIVIRAL DRUG DESIGN" must be typed in. Application forms may be obtained from the institution's office of sponsored research or its equivalent and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. Applications must address the requirements as outlined below. Applications from multi-component consortia must contain a single face page, an overall budget page, and separate budget pages for each institution involved. Each consortium institution is allowed 25 pages for the research plan if different plans are proposed by the different member institutions. For additional information, refer to page 8 of the PHS 398 application form. In addition to the instructions in the PHS 398, applicants must provide the following information for this RFA: 1. The research program proposed should describe plans to accommodate the RFA research objectives and goals. 2. Applications must name a single Principal Investigator (PI) who will have scientific responsibility for the application as a whole. 3. The application must include a written commitment to accept the participation and assistance of NIAID staff in accordance with the guidelines outlined under "Terms and Conditions of Award". 4. All costs required for the proposed protocol must be included in the application and must be fully justified. Requested budgets should also include travel to Bethesda, Maryland for the annual meeting. It is highly recommended that the Chief of the Antiviral Research Branch, Division of Microbiology and Infectious Diseases, NIAID be contacted in the early stages of preparation of the application. (See program contact in INQUIRIES below.) Applications must be received by August 10, 1994. All components, subparts and sections of the application must be collated into the application, and the packages sent to the DRG and to the NIAID must each be complete in themselves. Applications that do not conform to the instructions contained in PHS 398 (rev. 9/91) application kit will be judged non-responsive and will be returned to the applicant. The RFA label in the application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-spaced photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional exact copies of the grant application and all five sets of appendix material must also be sent to Dr. Olivia Preble at the address listed under INQUIRIES. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Review Method Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants (DRG) and for responsiveness by NIAID staff. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, it will be returned without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be promptly notified. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council in February 1995. Review Criteria The review criteria for this RFA are the same as those for unsolicited research project grant applications. In addition, applicants are expected to address criteria specific to the objectives of this RFA. The review group will assess the scientific merit of the applications on the basis of the following criteria: 1. Originality, novelty and scientific merit of research approach, design, and methodology as well as the potential scientific, technical, or medical significance of the proposed antiviral research. 2. Research experience and competence of the Principal Investigator and staff in molecular, structural, and/or antiviral research relevant to the proposed studies. 3. Adequacy of the time (effort) that the Principal Investigator and staff would devote to the proposed studies. 4. Adequacy of facilities. 5. Appropriateness of the proposed budget and duration to the proposed research. 6. Demonstrated willingness to work as part of a cooperative research effort with the Scientific Coordinator and to communicate with other awardees funded as a result of this RFA. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. It is the intent of DMID to fund applications that will ensure that a variety of approaches and virus systems will be investigated. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Catherine Laughlin, Ph.D.Chief, Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3A22 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8285 FAX: (301) 402-1456 Direct inquiries regarding review issues, address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Olivia Preble, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C19 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8208 FAX: (301) 402-2638 Direct inquiries regarding fiscal matters to: Ms. Barbara Huffman Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B26 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7075 FAX: (301) 480-3780 Schedule Letter of Intent Receipt Date: June 22, 1994 Application Receipt Date: August 10, 1994 Scientific Review Date: November 1994 Advisory Council Date: February 1995 Earliest Award Date: July 1995 AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Section 301 (c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assurance Citation is Sec. 93.856, Microbiology and Infectious Diseases Research. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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