Current Topics in Medicinal Chemistry, Volume 3, No. 6, 2003
Contents
Chemical
Biology and Chemical Genetics
Guest
Editors: Gustavo R. Rosania / Young-Tae Chang
Small-Molecule
Inhibitors of Actin Dynamics and Cell Motility Pp. 593-616
Gabriel Fenteany and Shoutian Zhu
Recent Advances
in Glycomics and Glycogenetics
Pp. 617-643
Sonya M. Khersonsky, Christine M. Ho, Mary-anne F.
Garcia and Young-Tae Chang
Custom
DNA-Binding Proteins and Artificial Transcription Factors Pp. 645-657
Dong-ki Lee, Wongi Seol and Jin-Soo Kim
Supertargeted
Chemistry: Identifying Relationships Between Molecular Structures and their
Sub-Cellular Distribution
Pp. 659-685
Gustavo R. Rosania
Micro- and
Nanotechnologies for Studying Cellular Function Pp. 687-703
Jeongsup Shim, Tommaso F. Bersano-Begey, Xiaoyue Zhu,
Alan H. Tkaczyk, Jennifer J. Linderman, and Shuichi Takayama
Array-Based
Technologies and their Applications in Proteomics Pp. 705-724
Grace Y. J. Chen, Mahesh Uttamchandanib, Rina Y. P.
Lueb, Marie-Laure Lesaicherre and Shao Q. Yao
Embryonic Stem
Cells: A Perfect Marriage Between Gene Regulation and Regenerative Medicine Pp. 725-737
Peng Zhou and Danith H. Ly
[Back to top] Small-Molecule
Inhibitors of Actin Dynamics and Cell Motility
Gabriel Fenteany and Shoutian Zhu
Cell motility is a central
feature of a range of normal and pathological processes, including embryonic development,
tissue repair, immune cell function, angiogenesis, and cancer metastasis. The
dynamics of the actin cytoskeleton power cell migration. A large number of
proteins are known or suspected to play roles in regulating actin dynamics.
While there are now many available small molecules that target the actin
cytoskeleton directly, there is a paucity of specific inhibitors of
actin-binding proteins and other immediate regulators of actin dynamics and
cell movement. This makes the field of exceptional interest as a meeting place
between the goals of chemical biology and the needs of cell biology.
Furthermore, while regulators of the cell cycle have been recognized for some
time as targets for anti-cancer drug development, controlling actin dynamics
and cell motility as a therapeutic approach has received scant attention in
comparison until recently. This review deals with small-molecule inhibitors of
actin dynamics as they relate to cell shape change and motility, from compounds
targeting actin directly to those targeting proteins involved in the
fundamental control of the actin cytoskeleton.
[Back to top] Recent Advances
in Glycomics and Glycogenetics
Sonya M. Khersonsky, Christine M. Ho, Mary-anne F.
Garcia and Young-Tae Chang
As the human genome sequence is
nearly deciphered, it is important to turn the attention to the physiological
functions of the genes. Thus, the study of the gene products, the proteins, is
the next big challenge. The proteins, however, are not the final gene products
in many cases. It has been shown that carbohydrates participate in
posttranslational modifications and in many other functional regulations, hence
the study of the glycome, the entire collection of carbohydrates is essential
in order to determine the functions of all genes, and will greatly enhance the
field of chemical genetics. Known biological function / targets of
carbohydrates and combinatorial synthesis & structural analysis of natural
/ non-natural carbohydrates are surveyed in this review. Methods to search for
new biological targets that include carbohydrate mimetics and carbohydrate
scaffolds along with chip technology, are also presented.
[Back to top] Custom
DNA-Binding Proteins and Artificial Transcription Factors
Dong-ki Lee, Wongi Seol and Jin-Soo Kim
Expression of the genome is
primarily regulated at the level of transcription by gene-specific
transcription factors, which recognize specific DNA sequences to activate or
inhibit transcription. The ability to control gene expression at will would
provide scientists with a powerful tool for biotechnology and drug-discovery
research. Over the last decade or so, researchers have made great strides in
our understanding of the structures and mechanisms of action of naturally
occurring transcription factors. Such research has revealed that members of the
Cys2-His2 zinc finger family of transcription factors consist of functional
modules that recognize a wide variety of DNA sequences. This review describes
recent advances in the development of novel methods to design and construct
artificial transcription factors to control gene expression at will. The
applications of artificial transcription factors in the areas of medicine and
biotechnology are discussed.
[Back to top] Supertargeted
Chemistry: Identifying Relationships Between Molecular Structures and their
Sub-Cellular Distribution
Gustavo R. Rosania
Supertargeted chemistry is the
study of how chemical structures localize or direct molecules to specific
sub-cellular compartments in living cells. Supertargeting can be used to
increase the activity or specificity of an inhibitor against its target, by
concentrating the inhibitor in the particular organelle where the target is
active. But, unlike structure-activity relationships, structure-localization
relationships are not a simple function of compound concentration. Various
aspects of mitochondrial physiology, proteomics and pharmacology have made this
the organelle of choice for supertargeting studies. While exploration of
supertargeting strategies to this and the other organelles has been limited,
combinatorial chemical libraries of fluorescent molecules are beginning to
illuminate new supertargeting mechanisms at the sub-cellular level. Moreover,
predictive approaches that determine the relationship between a molecule’s
features and sub-cellular localization are being developed in the related field
of functional genomics. Applied to the small molecules, such strategies could
prove useful for predicting structure-localization relationships amongst large
libraries of compounds.
[Back to top] Micro- and
Nanotechnologies for Studying Cellular Function
Jeongsup Shim, Tommaso F. Bersano-Begey, Xiaoyue
Zhu, Alan H. Tkaczyk, Jennifer J. Linderman, and Shuichi Takayama
The study of complex biological
systems requires methods to perturb the system in complex yet controlled ways to
elucidate mechanisms and dynamic interactions, and to recreate in vivo
conditions in flexible in vitro set-ups. This paper reviews recent advances in
the use of micro- and nanotechnologies in the study of complex biological
systems and the advantages they provide in these two areas. Particularly useful
for controlling the chemical and mechanical microenvironments of cells is a set
of techniques called soft lithography, whereby elastomeric materials are used
to transfer and generate micro- and nanoscale patterns. Examples of some of the
capabilities of soft lithography include the use of elastomeric stamps to
generate micropatterns of protein and the use of elastomeric channels to
localize chemicals with subcellular spatial resolutions. These types of biological
micro- and nanotechnologies combined with mathematical modeling will propel our
understandings of cellular and subcellular physiology to new heights.
[Back to top] Array-Based
Technologies and their Applications in Proteomics
Grace Y. J. Chen, Mahesh Uttamchandanib, Rina Y. P.
Lueb, Marie-Laure Lesaicherre and Shao Q. Yao
Latest microarray-based
technologies, including small molecule-, peptide-, protein- and cell-based
arrays, and their applications in the field of proteomics are reviewed.
[Back to top] Embryonic Stem
Cells: A Perfect Marriage Between Gene Regulation and Regenerative Medicine
Peng Zhou and Danith H. Ly
The mechanism of mammalian gene regulation
is highly complex, involving multiple layers of feedback control loops and
dynamic chromatin remodeling. The current approach used to dissect the genetic
circuitry of mammalian gene regulation utilizes somatic cells and protein
fusion as a means to modulate protein interactions. This approach has several
limitations that include (i) genome inaccessibility, (ii) high background
interferences and, (iii) limited cellular phenotypes. Previously, the two broad
fields of research “control of gene expression” and “stem cell biology” had
been pursued separately by cell biologists; this review outlines evidence
suggesting that integration of these two fields would provide a comprehensive
platform for interdisciplinary research seeking to address mechanistic
questions concerning gene regulationthat could have enormous implication for
the development of therapeutic applications.