YSM Issue 91.1

organic chemistry
FOCUS
lem and often occurs through mechanisms
that limit a drug’s accessibility to its biomolecular
target. Tuberculosis PTPs are intriguing
because the bacteria secrete these
enzymes, rendering them much more accessible
than the targets of most tuberculosis
drugs, which reside within bacterial cells.
However, additional research is needed to
validate mPTPA and mPTPB as drug targets,”
Ellman remarked.
This work also addressed a key problem
in PTP inhibitor development. Namely,
there is a high amount of structural similarity
among PTPs that makes it difficult
to achieve high selectivity of their developed
inhibitors. The researchers evaluated
the selectivity of their mPTPA inhibitor
against a collection of known human PTPs,
and also a generic cysteine protease, which
is an enzyme that breaks down proteins using
a key cysteine amino acid found within
the protein of interest. Here they found that
their mPTPA inhibitor had great selectivity
against each enzyme in this panel, indicating
that their inhibitor could act in a controlled
and predictable manner.
Drug efficacy in a biological setting
After testing their PTP inhibitors in a testtube
setting, the next step was to evaluate their
prodrug in a cellular context. However, in animal
models, it was found that both mPTPA
and mPTPB inhibitors were needed for significant
antibacterial activity. Because they
chose only to develop an inhibitor against
mPTPA at this stage of their research, they instead
decided to develop selenosulfide prodrug
inhibitors to another PTP target in order
to do a more simple and straightforward analysis
of the prodrug activity in the cell.
The second target, STEP, is a central nervous
system (CNS)-specific tyrosine phosphatase
that may be a therapeutic target for
neurological disorders like Alzheimer’s disease.
After testing a variety of potential prodrugs,
they identified one that could inhibit
STEP in rat cortical neurons.
After demonstrating the activity and specificity
of their PTP inhibitors, they reported
their success in developing a prodrug strategy
to facilitate the delivery of a novel class of
PTP inhibitors into cells in an efficient manner.
Their development of inhibitors for two
PTPs that can selectively inhibit mPTPA and
STEP very potently also acted as a robust
ABOUT THE AUTHOR
IMAGE COURTESY OF WIKIPEDIA
Protein tyrosine phosphatase (PTP), shown here, is a target for treatment for several diseases
including diabetes, cancer, and neurodegenerative disorders. Researchers at Yale have designed a
method for delivering PTP inhibitors in order to restore balance of tyrosine phosphorylation levels
within our cells.
proof-of-concept demonstration, showing
that their strategy for targeting PTPs is feasible
and has great potential.
Future promises of PTP-inhibitor drugs
In the future, Ellman hopes to expand
upon this research. “We intend to investigate
a number of questions to advance the
approach. For example, we will evaluate proteome-wide
specificity of identified inhibitors,”
he said. Of the inhibitors developed
in his lab so far, their group will need to see
how these inhibitors act across the entire
proteome, which is the collection of all proteins
present in our cells. In doing so, they
can determine if the inhibitor acts on a different
protein or group of proteins that was
not anticipated, which could have severe
consequences if the inhibitor targeted a protein
essential for our survival.
Furthermore, Ellman hopes to expand
upon the collection of PTP inhibitors already
developed in his lab. “We additionally
intend to test the generality of the approach
by developing potent and selective inhibitors
of other PTPs as well as other enzymes,”
Ellman said. If successful, this could result
in a greater number of potential drugs for
disease treatment involving PTP inhibition.
For example, some PTPs have been implicated
in cancer, and inhibitors of these enzymes
have been suggested as potential
drug candidates to be used in combination
with immunotherapy treatments. Although
such treatments would require more study
and clinical tests, the future of cancer treatment
using PTP inhibitors remains promising.
The use of PTP inhibitors extends
beyond cancer treatment, having vast implications
in both neurodegenerative disorders
and diabetes, two diseases with wide prevalence
in society that warrant crucial further
research and drug development.
MINDY LE
MINDY LE is a junior in Ezra Stiles College studying Molecular, Cellular, and Developmental
Biology. She is an avid squirrel enthusiast who works in Professor Patrick Sung’s lab, researching
DNA repair in the context of breast and ovarian cancer.
THE AUTHOR WOULD LIKE TO THANK both Professor Jonathan Ellman and Caroline Chandra Tjin
for their time and dedication to their research.
FURTHER READING
Tonks, N. K. 2013. “Protein tyrosine phosphatases--from housekeeping enzymes to master regulators of
signal transduction.” FEBS J. 280: 346-378.
www.yalescientific.org
March 2018
Yale Scientific Magazine
17