Full Text GM-96-012
NIH Guide, Volume 25, Number 26, August 2, 1996
RFA:  GM-96-012
P.T. 34

  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
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.
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).
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.
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.
This RFA is a one-time solicitation, and represents a request for
competing renewal applications funded under RFA GM-91-02 (STRUCTURAL
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.
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.
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
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.
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
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.
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.
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
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
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.
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.
Awards will be made according to priority score availability of
funds, and programmatic priorities.
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
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
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
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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