Full Text GM-96-012 STRUCTURAL BIOLOGY OF AIDS RELATED PROTEINS NIH Guide, Volume 25, Number 26, August 2, 1996 RFA: GM-96-012 P.T. 34 Keywords: AIDS Drug Design Proteins and Macromolecules National Institute of General Medical Sciences Letter of Intent Receipt Date: November 18, 1996 Application Receipt Date: December 18, 1996 PURPOSE The National Institute of General Medical Sciences (NIGMS) reannounces its interest in receiving applications to apply modern methods of molecular structure determination and analysis in developing new approaches to structure-based drug design. The intent is to develop new approaches to the treatment of AIDS and associated opportunistic infections. 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), Structural Biology of AIDS Related Proteins, is related to the priority area of HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, 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. Foreign organizations are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The mechanism of support will be the program project grant (P01). The circumstances under which NIGMS will support this RFA are the same as those described in the notice, "Support of Program Project Grants," published in the NIH Guide, Vol. 25, No. 10, March 29, 1996. It is expected that three or more investigators, all pursuing independent, interrelated projects, will be involved. One scientist must be designated by the applicant institution as the Principal Investigator and must bear the responsibility for the scientific and fiscal management of the program project grant. Most of the collaborating scientists should be independent investigators in accordance with the NIGMS program project notice cited above. Equipment and other core resources necessary for the accomplishment of the objectives of the program project grant may be requested. This RFA is one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE This RFA is a one-time solicitation, and represents a request for competing renewal applications funded under RFA GM-91-02 (STRUCTURAL BIOLOGY AS APPLIED TO THE PROBLEM OF TARGETED DRUG DESIGN, WITH POTENTIAL APPLICABILITY TO THE TREATMENT OF AIDS), and an opportunity for new groups to apply. The estimated funds (total costs) available for the first year of support for the entire program is $8,000,000. It is anticipated that six to ten applications will be funded. The level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. The total project period for applications submitted in response to this RFA may not exceed five years. The anticipated award date will be July 1, 1997. Although this program is provided for in the financial plans of NIGMS, the award of grants pursuant to this RFA is contingent on the availability of funds for this purpose. RESEARCH OBJECTIVES Background In 1987 the NIGMS initiated a program to support groups interested in developing the area of structure-based drug design with a specific emphasis on AIDS related systems. Since that time, considerable progress has been made through this program as well as elsewhere at NIH and in industry. The structures of several HIV proteins have been determined. These structures include the HIV, SIV and FIV proteases, the HIV reverse transcriptase, the zinc finger domains of the HIV nucleocapsid protein, and the catalytic domain of integrase. The first generation of HIV protease inhibitors have either been approved or are awaiting approval by the FDA. Other Although this progress has been significant, many areas require further investigation. For example, some targets, such as the membrane-bound gp120/gp41 complex, have not yielded to detailed structural determination. As another example, the development of drug resistance and complications raised by opportunistic infections present new challenges. Finally, despite the major advances that have been made in the speed with which structures can be determined and in our understanding of the theoretical basis of ligand binding to proteins, the limiting step in the process of drug design remains the lack of generalizable, efficient and reproducible approaches to the use of macromolecular structures to design lead compounds. Consequently, we are encouraging applications from research groups with an interest in developing the concepts and methodologies of structure-based drug design. Because of the progress that has been made in the determination of the structures of either AIDS-related proteins or proteins key to the survival of organisms that commonly cause opportunistic infections in people infected with HIV, it is expected that these will serve as a test bed for any new methodologies developed. Other possible targets that can be considered are biological macromolecules from the host that are involved in the uptake, transport, and integration of the viral genome. Furthermore, since drug resistance is now well-established as a major problem, the ability of potential inhibitors to withstand the effects of mutations of the target should be included in design principles. The central disciplines covered by this RFA are x-ray crystallography, NMR and molecular modeling augmented by expertise in organic synthesis, molecular enzymology, and virology. Groups with well-established expertise in this broad area but which have not previously been involved in AIDS research are encouraged to apply. SPECIAL REQUIREMENTS Informal interaction and exchange of information among all program groups is expected. All awardees are expected to participate in an annual conference. Because of the need for rapid communication of data, the three dimensional coordinates of structures determined as part of this program must be available in the Protein Data Bank at the time of publication. The National Institute of General Medical Sciences places a limit of $4 million in direct costs over five years that may be requested on all program project grants. Amounts over this total may be requested for major pieces of equipment, extensive organic synthesis, or other exceptional needs. Such exceptions must be discussed prior to submission with Dr. James Cassatt at the address listed under INQUIRIES. 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 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 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by November 18, 1996, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application the information contained allows NIGMS staff to estimate the potential review workload and avoid conflicts of interest in establishing the review panel. The letter of intent is to be sent to Dr. James C. Cassatt at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS-398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research; from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov; and from the NIH Program Director listed under INQUIRIES. The RFA label available in the application kit 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. In addition, the title of the application and the RFA number must be typed on line 2 of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies in one package to DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, SUITE 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to Helen R. Sunshine, Ph.D. Office of Scientific Review Activities National Institute of General Medical Sciences 45 Center Drive, MSC-6200 Bethesda, MD 20892-6200 Applications must be received by December 18, 1996. If an application is received after that date, it will be returned to the applicant without review. 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 substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by DRG staff for completeness and by NIGMS for responsiveness. Incomplete and/or non-responsive applications will be returned to the applicant. It should not be assumed that a site visit will be conducted during the course of the review of any of these applications. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory General Medical Sciences Council. Review criteria for this RFA are the same as for individual research grants. In particular the following aspects will be stressed: o Quality and originality of the proposed research projects, and the qualifications of the individual project leaders; o Involvement of investigators having expertise in the appropriate scientific disciplines to provide the breadth needed for an integrated program; o Evidence of collaboration and interaction among all the groups named in the application; and o Experience and competence of the Principal Investigator in directing and overseeing a broad program of the type proposed. AWARD CRITERIA Awards will be made according to priority score availability of funds, and programmatic priorities. INQUIRIES Written and telephone inquiries concerning this RFA are strongly encouraged. Preapproval is required for all new applications that request over $500,000 direct cost in any given year as noted above. Inquiries regarding programmatic issues and requests for prior approval may be addressed to: James C. Cassatt, Ph.D. Division of Cell Biology National Institute of General Medical Sciences 45 Center Drive, MSC-6200 Bethesda, MD 10892 Telephone: (301) 594-0828 FAX: (301) 480-2004 Email: czj@cu.nih.gov For fiscal and administrative matters contact: Phyllis Finch National Institute of General Medical Sciences 45 Center Drive, MSC-6200 Bethesda, MD 20892 Telephone: (301) 594-5243 Email: finchp@gm1.nigms.nih.gov Schedule Letter of Intent Receipt Date: November 18, 1996 Applications Receipt Date: December 18, 1996 Initial Review: March-April 1996 Secondary Review: May 1996 Anticipated Award Date: July 1, 1996 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Assistance No. 93-821. Awards will be made under the authority of the Public Health Service Act, Title IV, Part A, (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 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 PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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