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Jack
Blazyk, Ph.D.
Professor of Biochemistry
Department of Biomedical Sciences
Associate Dean for Research and Grants
blazyk@ohiou.edu
234 Grosvenor Hall
740-593-1742
Fax: 740-593-2320 |
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Since
most living organisms are very similar at the
molecular level, it is difficult to find substances
that are lethal to certain organisms without being
harmful to others. Antibiotics, such as penicillin,
have revolutionized the practice of medicine over
the past fifty years since they can kill bacteria
without harming human cells. Unfortunately, many
bacteria have developed resistant to penicillin and
most other antibiotics. The widespread use of common
antibiotics has increased the number of resistant
organisms, posing a health risk and creating a
challenge to develop novel agents to thwart virulent
organisms.
Many animals can produce small antimicrobial
peptides that serve as part of their natural defense
system. One example is a family of peptides called
magainins that is synthesized in frog skin in
response to wounding. These peptides are lethal to a
wide range of microorganisms, including
Gram-positive and Gram-negative bacteria, fungi,
parasites, and enveloped viruses because they induce
leakage in the cell membrane. Some of these peptides
may even be able to attack tumor cells. Two
shortcomings of these natural compounds, however,
are that (1) very high peptide concentrations are
needed for antimicrobial efficacy and (2) the
difference in toxicity (therapeutic index) between
target and host cells is not sufficiently high for
systemic use.
A common feature of these peptides is their capacity
to form an amphipathic alpha-helix (with polar and
nonpolar groups on opposite faces of the helix), a
structural feature believed to be important in their
function as antimicrobial agents. Numerous analogues
with sequences derived from these peptides have been
prepared and examined. In nearly all cases, the
strategy employed in enhancing activity involved
increasing the amphipathic alpha-helical character
of the peptide.
We designed a new type of linear peptide that is
structurally distinct from the natural defense
peptides. These peptides have no potential to form
an amphipathic alpha-helix, but can form a highly
amphipathic beta-sheet. Our new peptides have high
antimicrobial activity and are much more selective
for bacterial membranes vs. mammalian membranes as
compared to the natural peptide design. Ohio
University recently filed a patent application for
this new class of antimicrobial peptides.
Our initial NIH funding allowed us to study the role
of peptide conformation in antimicrobial potency and
selectivity. Until now, no one had attempted a
comprehensive study of the structure-function
relationships of families of closely related linear
peptides with simple sequences that were designed to adopt
different secondary structures. This approach revealed the importance of amphipathic
character in determining antimicrobial activity and
selectivity between bacterial and mammalian
membranes.
Using the two families of peptides with varying
capacity to form amphipathic alpha-helical and
beta-sheet structures, we investigated the
following areas: 1) the relationship of secondary
structure and amphipathic character of the peptides
to antimicrobial activity; 2) the amount of peptide
that must bind to the membrane in order to induce
leakage; and 3) the role of the membrane lipid
composition in determining susceptibility to
peptide-induced increase in permeability.
These results were published recently in
Antimicrobial Agents and Chemotherapy.
Recently we created a collection of new smaller
linear amphipathic beta-sheet peptides with enhanced
potency. We are examining whether these peptides
work by the same mechanism as the larger
antimicrobial peptides and whether they have
potential for systemic use. In addition, antiviral
activity and the ability to selectively kill
transformed human cells at concentrations that are
not toxic to normal cells are under investigation.
Our ultimate goal is to design smaller, more
effective antimicrobial peptides that will augment
the arsenal of available antibiotics in order to
keep pace with the ever-increasing threat posed by
antibiotic-resistant bacteria and viruses.
This project has been supported by the
National Institute of Allergy and Infectious
Diseases (NIAID) since 2000 and funding was renewed in 2006. |
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