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NOVEL ANTI-INFECTIVE SMALL MOLECULES THAT TARGET RNA
Background:
UCSF researchers have synthesized and screened novel compounds, based
on a central chemical scaffold, which show binding to RNA structures
that are potential therapeutic targets for infectious and viral diseases.
RNA-based drug design will benefit the treatment of diseases that rely
on unique RNA structures that play essential roles in pathogen viability
and propagation. For example, HIV, a global health threat responsible
for millions of deaths worldwide, is a virus that requires unique RNA
structures that are necessary during the viral lifecycle. The development
of new methods for treating HIV infection is especially important because
of the fast mutation rate of HIV, leading to the widespread development
of resistance to existing medications. The development and spread of
resistance is also a problem with antibiotic treatments for many deleterious
bacterial diseases, including skin, bloodstream, and respiratory infections.
Resistance to existing antibiotics, many of which target RNA, has created
a need for new antibiotics. Novel compounds developed at UCSF show
activity against targets that may be involved in the spread of HIV
as well as bacterial and non-HIV viral diseases. This class of compounds
may also represent a scaffold that will prove useful for the development
of multiple anti-infective agents binding different RNA targets involved
in various disease states.
Description:
Screening of compounds that recognize the unique surfaces of proteins,
derived through combinatorial methods or through complementary design
against high-resolution structures, has led to many new therapeutic
agents. In addition to proteins, RNA also adopts unique structures
and has been the successful target of past pharmaceutical efforts.
The aminoglycosides, tetracyclines, and macrolides are just a few examples
of highly successful classes of antibiotics that target RNA. UCSF researchers
have developed and utilized a computational approach for the identification
of compounds that bind to the three-dimensional structures of selected
RNA targets. This method resulted in the identification of a chemical
scaffold that was further derivatized to generate novel RNA-binding
molecules that bind multiple RNA targets involved in human diseases.
HIV is a virus that
requires a unique RNA structure, the transactivation response element
(TAR), for transcription of the viral genome. UCSF has identified novel
compounds that block the interaction of TAR with the viral transactivation
protein, Tat. This interaction is necessary for proper replication
of the viral RNA genome; therefore, these novel lead compounds may
form the basis for new HIV treatments. The compounds developed to disrupt
the HIV Tat-TAR interaction inhibit the Tat-TAR interaction in vitro
and also exhibit inhibition of Tat activity in cell-based assays. In
addition, the compounds have been screened against RNA sequences representing
anti-bacterial and other anti-viral targets.
Through both rational
design and combinatorial efforts, an RNA-binding chemical scaffold
has been identified and derivatives have been synthesized which show
differential binding to multiple potential therapeutic targets. UCSF
researchers continue to synthesize and screen novel derivatives of
active compounds to improve both the affinity and selectivity of these
anti-infective lead compounds, for which patent rights are available.
Potential Applications:
- Novel therapeutic small molecules for HIV
- Novel anti-viral and anti-bacterial small molecules
- Novel chemical scaffold for design of additional therapeutics
Intellectual Property:
UCSF has filed a patent
application, which includes composition of matter and method claims,
on the above technology.
The publication of this application (WO/03062388)
can be found through the following
link.
If you would like to receive further information
about this technology and potential licensing opportunities, please
contact:
Elizabeth E. Bellocchio, Ph.D.
Licensing Officer
(415) 353-4469 phone
(415) 348-1579 fax
Elizabeth Bellocchio
Reference: OTM Case #SF01-111
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