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Innovation for Global Health
the symbiosis. This work demonstrates the value of geographic
considerations when prospecting for bioactive compounds and
the importance of approaching natural product synthesis as an
interaction between the source and its environment. Because a
third (Deep) sibling species of B. neritina has provided additional
bryostatins not found in Shallow animals, it is possible that Northern
B. neritina may serve as a source of novel bioactive compounds.
ABSTRACT 23
Screening of a Small Compound Array
Yields Methotrexate’s Ability to Protect
against Lethal Orthopoxvirus Challenge
VE Cadet 1,2 , F Michel 3 , X Gao 3 and RJ Hogan 2,3
1Department of Basic Science, Philadelphia College of Osteopathic
Medicine–GA Campus, Suwanee, GA USA; 2Department of
Infectious Diseases, College of Veterinary Medicine, University of
Georgia, Athens, GA USA; 3Department of Anatomy and Radiology,
College of Veterinary Medicine, University of Georgia, Athens,
GA, USA
BACKGROUND: Poxvirus zoonoses have been well documented
in recent years. Cowpox infected cats, rodents and cattle, in close
contact with humans, have been reported to transmit the virus
through open wounds, large respiratory droplets and fomites.
The emerging infectious pathogen monkeypox has been noted to
undergo serial human transmission. Vaccinia virus has been shown
time and again to be transmissible through direct physical and
indirect contact from recent vaccinees to unvaccinated individuals.
Typically, disease course is mild and self-limiting; however severe
generalized infections have been described in patients with atopic
dermatitis or immunosuppression. With the waning of specific
immunity in the general population combined with the severity
of complications occurring post orthopoxvirus infections in the
immunocompromised, the need for continued research and
development of therapies has been underscored.
METHODS: To address the deficiency of FDA-approved poxvirus
treatments, a small molecule library was screened for the purpose
of illuminating compounds which inhibit poxvirus multiplication.
Two independent screens of n=446 compounds were carried
out in Vero E6 cells using cowpox as the representative poxvirus.
Compounds identified in the primary screen were rescreened in
a dose-dependent manner and four hits identified. Subsequent
validation in type II pneumocytes was carried out and methotrexate
chosen for in vivo analysis to assess protection against an intranasal
cowpox infection in BALB/c mice.
RESULTS: We have identified four compounds, each currently in
use as chemotherapeutics and/ or immunosuppressives, which
protect against viral multiplication in vitro at concentrations as low
as 0.04 micromolar: methotrexate, idarubicin, homoharringtonine
and raltitrexed. Methotrexate proved effective at prolonging mice
survival as well as limiting viral multiplication in the lungs.
CONCLUSIONS: These results identify methotrexate as a compound
with anti-poxvirus capability from which derivatives can be studied
for potential administration to protect against human orthopoxvirus
infections. They also highlight several other potential compounds
which can be further explored for in vivo protective efficacy in
future studies.
2012 Georgia Life Sciences Summit
ABSTRACT 24
Novel zinc binding group (ZBG) for
selective histone deacetylase inhibition.
Q Sodji 1 , V Patil 1 , A Oyelere 1 , J Kornacki 2 and M Mrksich 2
1School of Chemistry and Biochemistry, Georgia Institute of
Technology, Atlanta, GA, USA; 2Department of Chemistry,
Northwestern University, Evanston, IL, USA
Histone deacetylase inhibitors (HDACi) such as SAHA (Vorinostat)
have recently been approved by the Food and Drug Administration
(FDA) for the treatment of cutaneous T-cell lymphoma (CTCL).
We have identified 3-hydroxy-pyridin-2-thione as a novel ZBG for
HDAC inhibition, and performed a structure activity relationship
(SAR).Biological studies were also conducted to validate the
mechanism of action of these compounds.
These compounds were HDAC6 or 8 selective inhibitors. Some
of the HDACi thus obtained were shown to possess anti-cancer
activities.
3-hydroxy-pyridin-2-thione represents a ZBG compatible with
HDACi pharmacophoric model
ABSTRACT 25
Modular Synthesis of Heparan Sulfate
Oligosaccharides
OP Dhamale 1 , KA Mafraji 1 , A Venot 1 and GJ Boons 1
1Complex Carbohydrate Research Center, University of Georgia,
Athens, GA, USA
Heparan sulfate (HS) belongs to the family of glycosaminoglycans
which are complex polysaccharides characterized by a repeat
disaccharide unit of uronic acid linked to glucosamine. HS is
decorated with negatively charged functionalities like carboxylates
and sulfates along its backbone and therefore has a high charge
density. The HS polysaccharides bear specific sequences within their
lengths that modulate selective interactions with proteins and these
interactions result in regulation of protein activation. Unlike protein
synthesis, HS biosynthesis is not template driven and many of its
enzymatic transformations do not go to completion which in turn
imparts a high degree of structural diversity. Although hundreds of
HS binding proteins have been identified, very little information is
known about the specific sequences within HS required for binding
and mediating biological activities of these proteins. This difficulty
results from a lack of synthetic technology for establishing structureactivity-relationships
between HS and proteins. To address this
deficiency, we have developed a modular approach for the parallel
combinatorial synthesis of HS oligosaccharides.
In this new approach a modular synthetic technology was
developed which uses a relatively small number of selectively
protected disaccharide building blocks, which were easily be
converted into glycosyl donors and acceptors for oligosaccharide
assembly. The use of a set of orthogonal amino-protecting groups
made it possible to prepare compounds that have combinations of
acetamido and N-sulfate moieties. The carboxylate functionality was
incorporated at the monosaccharide level, whereas the installation
of sulfates was done towards the end of the synthesis. The design
and direction of the synthesis was completely target oriented.
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