MOLECULAR AND STRUCTURAL APPROACHES TO ANTIVIRAL STRATEGY

Release Date:  March 20, 1998

PA NUMBER:  PA-98-045

P.T.

National Institute of Allergy and Infectious Diseases

PURPOSE

The Division of Microbiology and Infectious Diseases (DMID), National Institute
of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH),
invites applications proposing innovative basic research projects on selective
antiviral strategies.  The important areas include, but are not limited to: (1)
novel molecular and structural approaches (chemical or biological) to rational
drug design and discovery that utilize an understanding of viral genetics,
replication, and pathogenesis; (2) novel drug discovery through knowledge-based
screening of combinatorial libraries and natural products; and (3) novel
molecular approaches to drug delivery.  The virus targeted for intervention
should be a human pathogen or one that serves as a model for a human pathogen,
except for human immunodeficiency virus (HIV) and/or other lentiviruses.

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 PA, Molecular and Structural
Approaches to Antiviral Strategy, is related to the priority areas of maternal
and infant health, sexually transmitted diseases, immunization, chronic diseases
and infectious diseases.  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

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.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Traditional research project grant (R01) applications may be submitted in
response to this program announcement.  Applications for R01 grants may request
up to five years of support.  Responsibility for the planning, direction, and
execution of the proposed research will be solely that of the applicant.

RESEARCH OBJECTIVES

Background

The discovery and development of effective and safe antiviral therapies for the
treatment of human viral infections are among major scientific interests of the
DMID.  In 1988, the DMID issued a Request For Application (RFA) to solicit
applications proposing research on the design of antiviral agents that will
specifically inhibit a viral (or viral-induced) function and not interact with
cellular components. This RFA was recompeted in 1994 and 11 Cooperative
Agreements (U01s) were awarded.  These awards will expire July 1999.  In
recognition of the future need for new antiviral agents and recent advances in
chemistry and biology, this Program Announcement (PA) expands the goals of the
RFA to include other important basic antiviral research areas.  The goal of this
PA is to solicit investigator-initiated applications that address critical areas
or new opportunities in antiviral research.

Viral infections are significant causes of human mortality, morbidity, and
economic loss.  Although there are a limited number of antiviral therapeutic
agents available for the treatment of viral infections, the majority of viral 
infections are impossible to treat effectively, and many are serious health
concerns.  Currently, only fifteen antiviral therapeutic agents (idoxuridine,
trifluridine, acyclovir, valacyclovir, famciclovir, vidarabine, ganciclovir,
foscarnet, cidofovir, podofilox, amantadine, rimantadine, ribavirin, RSVIGIV, and
interferon) have been approved by the FDA for the treatment of a small number of
non-HIV viral diseases.  However, in many cases, their utility is limited by
toxicity or the emergence of resistant mutants.  Because many of these drugs have
the same mechanism of action, a simple mutation can result in cross-resistance
to a whole family of the drugs.  For example, emergence of thymidine kinase
deficient mutants of herpes simplex virus in immunocompromised patients renders
the three acyclic nucleosides for herpes simplex infections ineffective for the
treatment of these infected patients.  Amantadine and rimantadine share a common
mechanism of action, and influenza virus quickly develops resistance to both
drugs even in immunocompetent patients.  In addition to development of viral
resistance, cidofovir, ganciclovir and foscarnet, the three drugs approved for
CMV retinitis in AIDS patients, have significant toxicity.  Therefore, the
development of clinically effective and safe antiviral agents is essential for
the control of viral infections.

Viruses are intracellular pathogens sharing many of the nutritional requirements
and synthetic pathways of the host cells they infect.  Therefore, an ideal
antiviral agent will be one that effectively interdicts viral infection as a
consequence of interaction with a target that is unique to the virus, and hence
of little or no concern to the uninfected host tissues.  In principle, such
selective antiviral activity can be achieved by directing drugs toward virus-
specific genes, enzymes, or cellular receptors. Selectivity may also be possible
by interfering with virus replication via host mechanisms.  For example,
amantadine's anti-influenza activity is a consequence of its causing altered pH
in endocytotic vesicles.

Although most of the currently approved antivirals were discovered by random
screening, recent advances in the knowledge of the molecular details of virion
structures and viral replication have provided evidence that one can logically
apply such information for rational design and discover selective antiviral
drugs.  A recent dramatic example is the design of clinically effective
inhibitors based on the crystal structure of the HIV protease.  Recent
preliminary clinical trials have also shown encouraging results with inhibitors
of influenza neuraminidase and picornavirus capsid-binding interactions,
respectively. Antisense oligonucleotides targeting specific viral mRNA sequences
of HIV, human cytomegalovirus (HCMV), or human papillomavirus (HPV) are also now
in clinical trials.

Recent developments in chemistry and biology suggest molecules generated from
combinatorial libraries, isolated from natural products, and collected in
chemical databases represent a series of rich sources of novel diversified
chemical entities ready for drug discovery.  Knowledge-based searches of such
sources could lead to the discovery of active compounds with unanticipated
structures.

It is known that many potentially effective antivirals are intrinsically active
but associated with unacceptable systemic toxicity.  By employing novel
controlled delivery systems, one could achieve optimum therapeutic responses, 
prolonged efficacy, and decreased toxicity by, predictably and reproducibly,
transporting and releasing the drug to the specific target environment.

The antiviral agents designed and discovered by investigators supported by this
PA can be further evaluated by DMID-supported contractors who engage in
preclinical evaluation of potential antiviral compounds.  The contractors provide
in vitro screens to test compounds' cytotoxicity and activities in cell culture
systems against a variety of viruses. These include herpes viruses (herpes
simplex virus types 1 and 2, varicella zoster virus, human and murine
cytomegaloviruses, and Epstein-Barr virus), respiratory viruses (influenza virus
types A and B, respiratory syncytial virus, parainfluenza virus type 3, measles
virus, and adenovirus type 5), and hepatitis B virus.  Active compounds
identified in the in vitro screens can be further studied in the DMID-supported
animal models, which examine compounds' in vivo efficacy and toxicity and limited
pharmacokinetics.  These models mimic human viral diseases caused by herpes
simplex virus, cytomegalovirus, papillomavirus, influenza, parainfluenza,
measles, and hepatitis B virus.  The information obtained from the in vivo
experiments serve to guide the design of clinical trial protocols.

Research Objectives and Scope

The purpose of this PA is to stimulate research in the development of novel
molecularly targeted approaches to antiviral therapy.  This includes, but is not
limited to, strategies for the rational design and discovery of new agents with
novel mechanisms of action 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.

Viral-specific or virus-induced events in viral replication, pathogenesis, and
host interaction pathways could provide appropriate targets for selective
antiviral agents.  Important or new targets would then be utilized for new lead
generation and optimization.  The strategies include, but are not limited to:
molecular modeling and de novo design, quantitative structure-activity
relationships, computer-assisted structural searching, mechanism-based design,
and/or transport and receptor-based design.  Drug discovery may also be achieved
through exploiting molecular diversity generated from structure-based
combinatorial libraries (chemical or biological) and natural products coupled
with smart screening strategies.  Targeted approaches to drug delivery are also
encouraged since drug toxicity often results from effects on uninfected cells.

Collaborations between different scientific disciplines, such as chemistry and
virology, as well as collaborations between industrial and academic investigators
are encouraged.  Virus systems should be those (except HIV and related
lentiviruses) that provide a model for a clinically important human viral
infection.  The preferential choices include hepatitis C virus, hepatitis B
virus, papillomavirus, cytomegalovirus, influenza viruses, respiratory syncytial
virus, parainfluenza virus, dengue, coronavirus, rhinovirus, enterovirus, and
calicivirus.

It is possible that research proposals 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.  Proposals to conduct clinical trials will not be considered for this
PA.

SPECIAL REQUIREMENTS

Awardees will be requested to participate in an annual meeting of investigators
funded under this PA to discuss progress and strategies for future research. 
Costs to support this travel for the Principal Investigator, or a designated Co-
Investigator, should be included in the proposed budgetary estimate.  For
estimating purposes assume that the meeting will be held for two full days in the
Washington, DC metropolitan area.

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 are provided that inclusion is inappropriate with
respect to the health of the subjects of the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

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 the NIH Guide for Grants and Contracts, Vol. 23, No. 11,
March 18, 1994.

Investigators may obtain copies from these sources or from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application for PHS 398 (rev. 5/95)
and will be accepted on the standard application deadlines as indicated in the
application kit.  Application kits are available at most institutional offices
of sponsored research and may be obtained from the Division of Extramural
Outreach and Information, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email:
asknih@od.nih.gov.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES".  The PA number and the PA title must also be
typed in section 2.

The completed, signed original and five legible, single-sided copies of the
application and five copies of appendices must be sent or delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

Applicants from institutions that have a General Clinical Research Centers (GCRC)
funded by the NIH National Center for Research Resources may wish to identify the
Center as a resource for conducting the proposed research.  If so, a letter of
agreement from the GCRC Program Director must be included in the application
material.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be assigned on the basis of established PHS referral
guidelines.  Upon receipt, applications will be reviewed for completeness by the
NIH Center for Scientific Review.  Incomplete applications will be returned to
the applicant without further consideration.

Applications will be reviewed for scientific and technical merit by study
sections of the Center for Scientific Review, NIH, 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 the applications under review, will be discussed, assigned a priority
score, and receive a second level review by the appropriate national advisory
council.

Review Criteria

The five criteria to be used in the evaluation of grant applications are listed
below.  To put those criteria in context, the following information is contained
in instructions to the peer reviewers.

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.  Note that the
application does not need to be strong in all categories to be judged likely to
have a major scientific impact and thus deserve a high priority score.  For
example, an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.

1.  Significance.  Does this study address an important problem? If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator.  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific goals of the
research and plans for the recruitment and retention of subjects; the provisions
for the protection of human and animal subjects; and the safety of the research
environment.

AWARD CRITERIA

Applications will compete for available funds with all other favorably
recommended applications.  The following will be considered when making funding
decisions:  quality of the proposed project as determined by peer review, program
balance among research areas of the program announcement, and availability of
funds.

INQUIRIES

Written and telephone inquiries are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Inquiries regarding programmatic issues may be directed to:

Dr. Christopher Tseng
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3B10
Bethesda, MD  20892-7630
Telephone:  (301) 496-7453
FAX:  (301) 402-1456
Email:  ct23i@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Kathryn Phillips
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C24
Bethesda, MD  20892-7610
Telephone:  (301) 402-6579
FAX:  (301) 480-3780
Email:  kp18y@nih.gov

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service Act,
Sec. 301, as amended.  The Catalogue of Federal Domestic Assistance Citation is
No. 93.856 - Microbiology and Infectious Disease 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 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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