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) 435-0714.  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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