STRUCTURAL BIOLOGY
AND TARGETED DRUG DESIGN FOR AIDS
PROGRAM
OVERVIEW
The structure-based development of inhibitors
of key proteins of the human immunodeficiency virus (HIV) and of organisms
responsible for HIV-related opportunistic infections is proposed. Despite
the major advances made recently in the treatment of acquired immunodeficiency
syndrome (AIDS) it remains a major threat to the public health. Furthermore,
the widespread development of resistance to antibacterial and antiviral
drugs, the emergence of new diseases, and the escalating costs of drug
discovery and health care make the development of more rapid and efficient
drug discovery methods imperative.
The primary HIV targets to be used for
the development of inhibitors are integrase, Rev, and previously unexplored
sites on reverse transcriptase. A dominant negative approach to inhibition
of the HIV protease will also be pursued. In addition, two discovery efforts
will focus on protein targets of HIV-related opportunistic infections:
(a) the protease of HHV8, the Kaposi's sarcoma virus, and (b) the Mycobacterium
tuberculosis alkylhydroperoxidase. The alkylhydroperoxidase compensates
for loss of the katG peroxidase in isoniazid resistant strains and is a
new and exciting target for the treatment of drug resistant tuberculosis.
The proteins required for these studies
are currently produced by recombinant methods and are to be purified, crystallized,
and subjected to X-ray diffraction analysis. Mechanistic studies of the
less well characterized enzyme targets will be carried out to obtain the
information required for the design of reversible and irreversible inhibitors.
Structural and mechanistic information will be used in conjunction with
computational methods to identify potential inhibitors of the enzymes.
The inhibitor candidates will be synthesized, assayed with isolated enzymes,
and in some cases co-crystallized with the enzymes for structural analysis.
Inhibitor optimization will be assisted by computational approaches, and
the improvement of such approaches for the discovery and optimization of
drug candidates is one of the goals of this proposal. Promising drug candidates
will be evaluated in cell culture and in vivo. This broad, structure-based
attack on HIV and two major opportunistic infections should produce not
only potentially useful drug leads but also fundamental knowledge relevant
to the design of drugs for infectious agents.
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Projects
PROJECT # 1
NUCLEOTIDE PROCESSING AND REGULATION
Project Leader: Andrew D. Leavitt, M.D.
Section A
REVERSE TRANSCRIPTASE
Section Leader: George L. Kenyon, Ph.D.
Section B
INTEGRASE
Section Leader: Andrew D. Leavitt, M.D.
Section C
REV
Section Leader: Alan
D. Frankel, Ph.D., Associate Professor, Departments of Biochemistry
& Biophysics, and Cellular and Molecular Pharmacology
PROJECT #2
HIV PROTEASE AND OPPORTUNISTIC INFECTIONS
Project Leader: Charles
S. Craik, Ph.D. Professor, Department of Pharmaceutical Chemistry;
Associate Adjunct Professor, Department of Biochemistry & Biophysics
PROJECT # 2 Section B
KAPOSI SARCOMA PROTEASE
Section Leader: Charles S. Craik, Ph.D.
PROJECT # 2 Section C
MYOBACTERIUM TUBERCULOSIS AHPC
Section Leader: Paul
Ortiz de Montellano, Ph.D., Professor, Departments of Pharmaceutical
Chemistry and Biopharmaceutical Sciences
PROJECT # 3
STRUCTURAL BIOLOGY
Project Leader: Robert
M. Stroud, Ph.D., Professor, Departments of Biochemistry &
Biophysics, and Pharmaceutical Chemistry
PROJECT # 4
COMPUTATION
Project Leader: Irwin
D. Kuntz, Ph.D., Professor, Departments of Pharmaceutical Chemistry,
and Biochemistry & Biophysics;Director, Molecular Design Institute
CORE
ROBOTIC SCREENING
Core Leader: Charles S. Craik, Ph.D.
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UCSF
MOLECULAR DESIGN INSTITUTE
The Molecular Design Institute (MDI) serves
as the administrative focus for the UCSF PPG application. The MDI is an
Organized Research Unit (ORU) of the University of California, San Francisco.
The goal of the Molecular Design Institute is to promote and coordinate
research and education in the broad area of molecular design with particular
emphasis on drug design. Specifically, the MDI focuses on the development
of new methods to aid in the discovery of novel pharmaceutical agents.
A major focus is to bridge the existing academic disciplines and departments
to enhance progress in all aspects of this important area. The specific
aims of the MDI are:
To provide an inter-departmental organization
for the many research groups and projects at UCSF working on macromolecular
structure and molecular design.
To develop multidisciplinary collaborations.
To promote the external visibility of the
very strong UCSF research in computational, structural and molecular biology.
To provide a framework for the expansion of
pharmaceutical science, structural biology, biotechnology and toxicology
at UCSF.
To provide a center for technology transfer
to industry and to clinical medicine.
Structure-based molecular design applies the
principles of chemistry, medicinal chemistry, biochemistry and molecular
biology to the design and development of bioactive agents such as drugs.
Ideas from mathematics and computer science are also incorporated. The
result is a comprehensive approach that can be of great practical importance.
New approaches to molecular design have
attracted wide-spread attention throughout the academic community and the
chemical and pharmaceutical industry. The new initiatives come from the
perception that conventional approaches (e.g., screening of natural products)
have reached the point of diminishing returns in developing new pharmaceutical
agents. An equal driving force has been the major scientific advances that
have flowered in the past decade in areas such as protein crystallography,
magnetic resonance, pharmacokinetics and molecular biology. There have
been orders of magnitude improvement in computational simulations and computer
graphics. Taken together, the tools are in place for very significant advances.
UCSF has an outstanding reputation because
of its strengths in medicinal and computational chemistry, biochemistry,
molecular biology and academic and clinical medicine. UCSF has a paramount
position, nationally and internationally, in many of these activities,
but the expertise is spread amongst several departments in three different
schools. Traditional departmental structures do not adapt readily to new
technological advances. It would greatly strengthen this diverse community
to have a core entity to provide central facilities and to focus activities.
The Molecular Design Institute provides an intellectual and scientific
clearinghouse for faculty members from several departments. It will develop
facilities that would drive effective fundamental research in the structural
sciences and provide for the hands-on training of students, fellows, and
visiting scientists. Because molecular design projects are truly interdisciplinary,
the MDI can be expected to encourage and extend the current strong position
of UCSF.
An important role of the Molecular Design
Institute is to promote interactions with the pharmaceutical industry.
By providing a mechanism for frequent exchange of views and plans and by
bringing together a group of faculty members with experience in interacting
with the private sector, it can help coordinate faculty and administration
activities for long-term industry/campus relationships.
The Molecular Design Institute encourages
research in molecular structure, structural biology, medicinal chemistry,
molecular calculations, computer graphics, biopharmaceutics, enzymology,
toxicology, biotechnology and molecular medicine. The principles of physical
and organic chemistry will be applied to questions of macromolecular interactions
and the design of drugs. Some research areas of most interest are:
Molecular structure: determination of the
structure of molecules of medicinal interest using crystallographic and
magnetic resonance techniques.
Structural biology: interaction of structure
and function in molecular assemblies.
Medicinal chemistry: synthesis of novel compounds;
synthesis of analogs of active compounds; development of new synthetic
strategies.
Molecular calculations: prediction and modeling
of structures of bioactive molecules and macromolecules; development of
computer algorithms; database manipulations; studies of molecular energy
and molecular motion.
Computer graphics: development of molecular
display technology; interface programs; human engineering.
Biopharmaceutics: pharmacokinetics; distribution
and transport of biologically important compounds; toxicology.
Enzymology: identification and characterization
of key enzyme targets of medical interest; development of novel strategies
of enzyme inhibition.
Toxicology: identification and characterization
of drug toxicities; development of computer-assisted evaluation of toxicity.
Biotechnology: protein engineering; production
and purification of peptides, proteins and nucleic acids.
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UCSF-MDI
AIDS Program Project Grant