Mini-Reviews in Medicinal Chemistry, Volume 2, No. 5, 2002
Executive Editors: Masakatsu Eguchi / Michael Kahn
Mimetics of the Peptide b-Strand Pp.433-445
Matthew
P. Glenn and David P. Fairlie
Design, Synthesis, and Application of Peptide
Secondary Structure Mimetics
Pp.447-462
Masakatsu
Eguchi and Michael Kahn
Peptidomimetics and Peptide Backbone
Modifications Pp.463-473
Jung-Mo
Ahn, Nicholas A. Boyle, Mary T. MacDonald and Kim D. Janda
Src Homology-2 Inhibitors: Peptidomimetic and
Nonpeptide Pp.475-488
Tomi
K. Sawyer, Regine S. Bohacek, David C. Dalgarno, Charles J. Eyermann, Noriyuki
Kawahata,
Chester
A. Metcalf III, William C. Shakespeare, Raji Sundaramoorthi, Yihan Wang and
Michael G. Yang
Peptidomimetics and Angiogenesis Pp.491-506
Ralph
Mazitschek, Patrick Baumhof and Athanassios Giannis
Recent Advances in the Development of
Nonpeptide Somatostatin Receptor Ligands Pp.507-517
A.
Michael Crider
[Back to top] Mimetics of the Peptide b-Strand
Matthew
P. Glenn and David P. Fairlie
Bioactive structures of peptides represent important clues
for drug discovery and development although peptides themselves have
substantial limitations as drugs. One promising approach to overcoming the limitations
of peptides is to progressively replace amide bonds in peptides with
non-peptidic constraints that bring drug-like properties like stability and
bioavailability to the molecules. These constraints can also be used to mould
molecules into shapes which mimic key elements of protein secondary structure
that confer bioactivity to protein surfaces. Preorganizing a molecule into the
shape recognized by a receptor results in high
affinity binding though a considerable entropy saving and is an effective
approach to engineering highly bioactive drug leads. One peptide structure, the
extended beta strand, has only recently been identified as a fundamental
recognition element in physiological processes. Relatively few molecules have
been described as constrained mimics of extended peptide conformations. We now
summarize some approaches to mimicking peptide beta strands, and illustrate
these with examples of bioactive, stable and bioavailable molecules that are
conformationally biased to mimic the extended peptide beta strand.
[Back to top] Design, Synthesis, and Application of Peptide
Secondary Structure Mimetics
Masakatsu
Eguchi and Michael Kahn
The
secondary structure peptidomimetic approach is a rational way to develop novel
nonpeptide pharmaceutical agents based upon biologically significant
proteinaceous leads. A part of this approach elaborated in this laboratory over
the past ten years is reviewed along with the recent developments in this field.
[Back to top] Peptidomimetics and Peptide Backbone
Modifications
Jung-Mo
Ahn, Nicholas A. Boyle, Mary T. MacDonald and Kim D. Janda
The replacement of
the amide bond in a peptide backbone is a widely used form of peptide mimicry.
Several of the most common amide bond surrogates, including peptidomimetic work
done in this laboratory, and their biological applications are presented in
this review.
[Back to top] Src Homology-2 Inhibitors: Peptidomimetic
and Nonpeptide
Tomi K. Sawyer, Regine S. Bohacek, David C. Dalgarno, Charles J. Eyermann, Noriyuki Kawahata, Chester A. Metcalf III, William C. Shakespeare, Raji Sundaramoorthi, Yihan Wang and Michael G. Yang
The structural and
functional characterization of Src homology-2 (SH2) domains and their
relationship to catalytic proteins (e.g., kinases, phosphatases, and lipases)
or non-catalytic proteins (e.g., upstream adapters, and downstream transcription
factors) has significantly impacted our understanding of signal transduction
pathways and the identification of promising therapeutic targets for drug
discovery. Such SH2-containing proteins are known to be intimately involved in
the regulation of a number of cellular processes, including growth,
mitogenesis, motility, metabolism, and gene transcription. Molecular
recognition and biochemical selectivity exists for various SH2 domains based on
their binding to phosphotyrosine (pTyr) and contiguous C-terminal amino acids
of cognate protein ‘partners’ in a sequencedependent manner (i.e.,
~pTyr-AA1-AA2-AA3~) which result in the formation of signal transduction
protein complexes in cells. In recent years, drug discovery efforts have
advanced peptidomimetic and nonpeptide inhibitors of such protein-protein
interactions based on mimicking pTyr-containing peptide ligands as well as SH2
structure-based de novo design of nonpeptide templates that can capture key
binding sites on the target protein. Noteworthy are peptidomimetic and
nonpeptide inhibitors of Src, Lck, Grb2, PI-3K, and Zap70 from pioneering
efforts that led to the first examples of cellularly and in vivo active SH2
inhibitors. This mini-review highlights key achievements in SH2 inhibitor drug
discovery with an emphasis on peptidomimetic and nonpeptide lead compounds in
terms of structure-based design, key chemical and biological properties, and
proof-of-concept studies relative to further defining the role(s) of SH2
domains in signal transduction processes, cellular functions, and in vivo
disease models.
[Back to top] Peptidomimetics and Angiogenesis
Ralph
Mazitschek, Patrick Baumhof and Athanassios Giannis
Angiogenesis is
the sprouting of new blood capillaries from surrounding preexisting blood
vessels. This process is fundamental for embryonic development, wound healing
and inflammation. In healthy adults angiogenesis is of minor importance.
However, aberrant angiogenesis is essentially involved in disorders as diabetic
retinopathy, rheumatoid arthritis and tumor growth, and blocking angiogenesis
has emerged as a promising target for antagonizing these diseases. Therefore
the development of new anti-angiogenic drugs is of great interest in academic
and industrial research.
This review
focuses on the employment of peptidomimetics in inhibiting pathologic
angiogenesis. It will survey the individual aspects of angiogenesis where the
usage of peptidomimetics is favored and will consider the current progresses on
this field.
[Back to top] Recent Advances in the Development of
Nonpeptide Somatostatin Receptor Ligands
A.
Michael Crider
Somatostatin
(SRIF) is a cyclic peptide that occurs in two biologically active forms,
SRIF-14 and SRIF-28. These peptides inhibit the secretion of many other
peptides, including insulin and glucagon, function as neurotransmitters or
neuromodulators, and exhibit potent antiproliferative activity. Recent research
has led to the development of nonpeptide SRIF ligands with high affinity and
selectivity at all SRIF receptor subtypes. Additionally, the newly discovered
sst2 and sst3 antagonists will greatly facilitate our
understanding of these receptors. These novel nonpeptide SRIF agonists and
antagonists may have therapeutic potential in a variety of disease states.