Current Drug Targets, Volume 3, No. 2, 2002
Intracellular Targets of Antibacterial
Peptides Pp.101-106
M.
Cudic and L. Otvos, Jr.
Ribosomally Synthesized Antibacterial
Peptides in Gram Positive Bacteria Pp.107-122
Dzung
B. Diep and Ingolf F. Nes
Molecular Design of Bioconjugated Cell Adhesion
Peptide with a Water-Soluble Polymeric Modifier for Enhancement of
Antimetastatic Effect
Pp.123-130
Yoko
Yamamoto, Yasuo Tsutsumi and Tadanori Mayumi
Tuberculosis Drug Targets Pp.131-154
Ying
Zhang and L. Mario Amzel
Aspartic Proteinases in Disease: A Structural
Perspective Pp.155-173
J.
B. Cooper
The Central Role Played by Peptides in the
Immune Response and the Design of Peptide-Based Vaccines Against Infectious
Diseases and Cancer
Pp.175-196
D.
C. Jackson, A. W. Purcell, C. J. Fitzmaurice, W. Zeng, and D. N. J. Hart
[Back to top] Intracellular Targets of Antibacterial
Peptides
M. Cudic and L. Otvos, Jr.
The recent past
witnessed a decrease in the number of new antibacterial compounds approved by
the regulatory agencies and an almost complete lack of molecules killing
bacteria by novel mechanisms of action. The broad spectrum antimicrobial agents
currently on the market carry the potential, and indeed victims, of resistance
developed against them. The need for new types of antimicrobial drugs coincides
with the desire of developing lead molecules that act selectively on a single
strain, or perhaps on a few closely related strains. Such selectivity would
exclude the likelihood of the emergence of broad-range resistance.
Intracellular bacterial targets, most prevalently proteins needed for the life
cycle of bacteria, carry the potential to be a resourceful target for a new
family of antimicrobial compounds. Inhibition of proteinaceous functions
requires stereospecificity, and a drug structurally similar to the target
proteins themselves. Indeed, some antibacterial peptides show selective
inhibition of intracellular targets. A few native peptides and their designed
analogs appear to kill only a limited number of bacterial strains.
Identification of the binding sites on the target proteins would allow the
design of strain-specific antibacterial and antifungal peptides without the
fear of development of common resistance to these agents.
[Back to top] Ribosomally Synthesized Antibacterial
Peptides in Gram Positive Bacteria
Dzung B. Diep and Ingolf F. Nes
The emergence of multidrug-resistant pathogens that has caused a serious problem in hospitals worldwide, has intensified the search for novel drugs, in order to replace or to be used in complement with the existing antibiotics. In this connection much interest has been focused on a group of antimicrobial peptides, so-called bacteriocins. These antagonising peptides, which are gene-encoded in contrast to those made by multi-enzyme-complexes, share some common physico-chemical properties, such as being small, cationic, amphiphilic and often being membrane active. However, they differ greatly from each other in their primary sequence and exhibit an impressively large inhibitory spectrum which covers almost all bacterial genera, including many important pathogens and food-spoilage bacteria. Many of these peptides are produced by lactic acid bacteria, organisms which have been used by man from ancient time in diverse fermentation processes, to improve and/or prolong self-life of many food and feed products. Numerous bacteriocins have been purified and characterised in great detail, both at biochemical and genetic levels. Still, novel bacteriocins with new properties are reported in an increasing number in recent years. In this review we will give a brief status quo of the present knowledge on bacteriocin research; thus different aspects such as their diversity in nature, biochemical properties, modes of action, biosynthesis and genetics will be treated.
[Back to top] Molecular Design of Bioconjugated Cell
Adhesion Peptide with a Water-Soluble Polymeric Modifier for Enhancement of
Antimetastatic Effect
Yoko Yamamoto, Yasuo Tsutsumi and Tadanori Mayumi
The adhesive
interaction of tumor cells with various components of the extracellular matrix
(ECM), such as laminin and fibronectin appears to play a crucial role in tumor
metastasis. It has been reported that adhesive peptides, such as
Tyr-Ile-Gly-Ser-Arg (YIGSR) in laminin and Arg-Gly-Asp (RGD), inhibited
adhesion and invasion of various tumor cells to ECM in vitro, and exhibited
inhibitory effects on pulmonary metastasis of B16-BL6 melanoma cells in mice.
However, large doses of these peptides were required for significant
anti-metastatic effects in vivo, probably due to their rapid degradation by
various peptidases and their rapid excretion from the blood into the urine. To
overcome these problems, the development of an appropriate drug delivery system
(DDS) is required to improve in vivo stability and prolong plasma half-lives.
Several strategies such as peptide-cyclization and D-amino acid substation have
been reported to improve stability in blood by inhibiting enzymatic
degradation. However, even these approaches have proven insufficient to
overcome rapid renal clearance from the circulation. On the other hand,
bioconjugation with water-soluble polymeric modifiers could markedly prolong
the plasma half-lives by not only increasing peptidase resistance but also
impeding renal excretion. In addition, it is possible to strictly control the
in vivo pharmacokinetics of a peptide by introducing functional molecules with
targeting or slow release capacities to the polymeric modifier. In this review
we demonstrate with reference to our recent studies that bioconjugation of
adhesive peptides with the appropriate polymeric modifier can enhance
antimetastatic activity and may facilitate therapeutic use.
[Back to top] Tuberculosis Drug Targets
Ying Zhang and L. Mario Amzel
Despite the
availability of the BCG vaccine and chemotherapy, tuberculosis (TB) remains a
leading infectious killer worldwide. The recent rise of TB and especially the
alarming increase of drug-resistant TB call for urgent need to develop new
anti-TB drugs. Lengthy chemotherapy and increasing emergence of drug-resistant
strains pose a significant problem for effective control. The need for a
lengthy TB therapy is a consequence of the presence of persistent Mycobacterium
tuberculosis, not effectively killed by current anti-TB agents. A list of new
drug candidates along with proposed targets for intervention is described.
Recent advances in the knowledge of the biology of the organism and the
availability of the genome sequence provide a wide range of novel targets for
drug design. Gene products involved in controlling vital aspects of
mycobacterial metabolism, persistence, virulence and cell wall synthesis would
be attractive targets. It is expected that the application of functional
genomics tools, such as microarray and proteomics, in combination with modern
approaches, such as structure-based drug design and combinatorial chemistry to
biology-based targets, will lead to the development of new drugs that are not
only active against drug-resistant TB but also can shorten the course of TB
therapy.
[Back to
top] Aspartic Proteinases in Disease: A Structural
Perspective
J. B. Cooper
The aspartic
proteinases are a family of enzymes involved in a number of important
biological processes. In animals the enzyme renin has a hypertensive action
through its role in the renin-angiotensin system. The retroviral aspartic
proteinases, such as the HIV proteinase, are essential for maturation of the
virus particle and inhibitors have a proven therapeutic record in the treatment
of AIDS. The lysosomal aspartic proteinase cathepsin D has been implicated in
tumorigenesis and the stomach enzyme pepsin, which plays a major physiological
role in hydrolysis of acid-denatured proteins, is responsible for much of the
tissue damage in peptic ulcer disease. Since aspartic proteinases also play
major roles in amyloid disease, malaria and common fungal infections such as
candidiasis, inhibitors to these enzymes are much sought after as potential
therapeutic agents. In all aspartic proteinases, the catalytic aspartate
residues are involved in an intricate arrangement of hydrogen bonds involving a
solvent molecule which is presumed to be water. The catalytic mechanism is
thought to involve nucleophilic attack of the active site water molecule on the
scissile bond carbonyl generating a tetrahedral gem-diol intermediate. The
design of inhibitors generally involves the use of short oligopeptides
containing a transition state analogue which mimic this tetrahedral intermediate.
The application of structure-based drug design to members of the aspartic
proteinase family is the main subject of this review.
[Back to top] The Central Role Played by Peptides in the Immune Response and the Design
of Peptide-Based Vaccines Against Infectious Diseases and Cancer
D.
C. Jackson, A. W. Purcell, C. J. Fitzmaurice, W. Zeng, and D. N. J. Hart
Vaccines are one
of the most cost effective methods of improving public health thereby
increasing the quality of life. Prophylactic and therapeutic treatment by
vaccines can prevent infectious diseases and some cancers and could also be
used in the treatment of autoimmune disorders. An appreciation of this
potential has resulted in a burgeoning literature which not only describes the
scientific efforts being made into designing new and improved vaccines but also
drives the efforts being made by public health organizations world-wide in
delivering vaccines to the community. At the forefront of technologies being applied
to the design of vaccines is the use of synthetic peptides; the chemical
technologies used to assemble peptides have made great strides over the last
decade and assembly of hi-fidelity peptides which can be of high molecular
weight, multimeric or even branched is now almost routine. Together with the
advances in peptide technology our understanding of the molecular events that
are necessary to induce immune responses has also made great strides. The
central role that peptides play in immune recognition is now recognised and
rules are emerging that are being applied to the construction of peptide-based
vaccines that, in the right context, can induce humoral (antibody) and cellular
(cytotoxic and helper T cell) immune responses. Synthetic peptides are exquisitely
placed to answer questions about immune recognition and along the way to
provide us with new and improved vaccines.