Current Drug Targets, Volume 4, No. 5, 2003
Contents
Fibroblast Growth Factor Receptor-3 as a
Therapeutic Target for Achondroplasia - Genetic Short Limbed Dwarfism Pp.353-365
David
Aviezer , Myriam Golembo and Avner
Yayon
Hepatoma Derived Growth Factor is a Nuclear
Targeted Mitogen Pp.367-371
Allen
D. Everett , and John Bushweller
Di/tri-Peptide Transporters as Drug Delivery
Targets: Regulation of Transport Under Physiological and Patho-physiological
Conditions Pp.373-388
Recent Strategies in the Search for New
Anti-Influenza Therapies
Pp.389-408
J.C.
Wilson and M. von Itzstein
Nuclear Import of the Pre-Integration Complex
(PIC): The Achilles Heel of HIV ? Pp.409-429
S.
C. Piller, L. Caly , and D. A.
Jans
Virally Encoded G Protein-Coupled Receptors:
Targets for Potentially Innovative Anti-Viral Drug Development Pp.431-441
Smit,
M.J. , Vink, C. , Verzijl, D., Casarosa, P.,
Abstracts
[Back to top] Fibroblast Growth Factor Receptor-3 as a
Therapeutic Target for Achondroplasia - Genetic Short Limbed Dwarfism
David
Aviezer , Myriam Golembo and Avner
Yayon
Achondroplasia,
the most common form of human dwarfism is a sporadic autosomal dominant
condition that occurs in approximately 1:20,000 births. The major clinical
outcome of Achondroplasia is attenuated growth, rhizomelic shortening of the
long bones and craniofacial abnormalities. As of today there is no
pharmacological treatment for Achondroplasia. Some improvement in the patients
well being and daily function can be achieved by a surgical limb lengthening
procedure. Growth hormone treatment seems to have only modest short term
success and to lack long term benefits. Achondroplasia results from a single
point mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). In 97% of the
patients, there is a Glycine to Arginine substitution at position 380 within
the FGFR-3 transmembrane domain leading to receptor overactivation. This FGF
receptor tyrosine kinase is expressed by chondrocytes in the growth plate of
developing long bones and plays a crucial role in bone growth. Genetic
disruption of the FGFR-3 gene in mice leads to a remarkable increase in the
length of the vertebral column and long bones. This suggests that overaction of
FGFR3 signaling may specifically impair chondrocyte function within the
epiphyseal growth plates and cause Achondroplasia. Reconstituted normal bone
growth may therefore be achieved by attenuation of FGFR3 signaling in the
appropriate cells within the growth plate. It is highly conceivable that drug
development strategies aimed either towards blocking extracellular ligand
binding or towards intracellular checkpoints along the FGF signal transduction
cascade, may prove successful in the treatment of Achondroplasia. This review
focuses on the possible approaches for developing a drug for Achondroplasia and
related skeletal disorders, using chemical, biochemical and molecular
strategies.
[Back to top] Hepatoma Derived Growth Factor is a Nuclear
Targeted Mitogen
Allen
D. Everett , and John Bushweller
Hepatoma Derived
Growth Factor (HDGF) was originally identified as a secreted mitogen from the
human hepatoma cell line Huh-7. Although initially thought to be a cytoplasmic
protein, it became clear that HDGF is a nuclear targeted protein containing a
canonical bipartite nuclear localization sequence. In the developing
vasculature HDGF is highly expressed in the nucleus of smooth muscle and
endothelial cells. HDGF expression in smooth muscle in particular, declines
after birth in larger arteries only to be re-expressed with vascular injury in
cells of the highly proliferative neointima. In addition, levels of HDGF have
recently been shown to be elevated in a number of cancers, suggesting a
potential role in cancer development. Because of these roles, HDGF is a
potential target for drug design. This review will describe current knowledge
about the biochemical functioning of the protein and identify potential avenues
for drug development.
[Back to top] Di/tri-Peptide Transporters as Drug Delivery
Targets: Regulation of Transport Under Physiological and Patho-physiological
Conditions
C.U.
Nielsen and B. Brodin
Two human
di/tri-peptide transporters, hPepT1 and hPepT2 have been identified and
functionally characterized. In the small intestine hPepT1 is exclusively
expressed, whereas both PepT1 and PepT2 are expressed in the proximal tubule.
The transport via di/tri-peptide transporters is proton-dependent, and the
transporters thus belong to the Proton-dependent Oligopeptide Transporter
(POT)-family. The transporters are not drug targets per se, however due to
their uniquely broad substrate specificity; they have proved to be relevant
drug targets at the level of drug transport. Drug molecules such as oral active
b-lactam antibiotics, bestatin, prodrugs of
aciclovir and ganciclovir have oral bioavailabilities, which largely are a
result of their interaction with PepT1. In the last few years an increasing
number of studies concerned with regulation of di/tri-peptide transporter
capacity have appeared. Studies on receptor-mediated regulation has shown that
both PepT1 and PepT2 is down-regulated by long-term exposure to epidermal
growth factor (EGF) due to a decreased gene transcription. PepT1-mediated
transport is upregulated by certain substrates and in response to fasting and
starvation at the level of increased gene transcription. PepT1-mediated
transport is up-regulated by short-term exposure to receptor agonists such as
EGF, insulin, leptin, and clonidine, and down-regulated by VIP. Overall, the
regulation of di/tri-peptide transport may be contributed to 1) changes in
apical proton-motive force 2) recruitment of di/tri-peptide transporters from
vesicular storages 3) changes in gene transcription/ mRNA stability. The aim of
the present review is to discuss physiological, patho-physiological and
druginduced regulation of di/tri-peptide transporter mediated transport.
[Back to top] Recent Strategies in the Search for New
Anti-Influenza Therapies
J.C.
Wilson and M. von Itzstein
Influenza is a
highly contagious, acute upper respiratory tract disease caused by influenza
virus, a member of the Orthomyxoviridae family. The viral particles have two
surface antigens, haemagglutinin and sialidase (neuraminidase) that extensively
decorate the surface of the virus and have been implicated in viral attachment
and fusion, and the release of virion progeny, respectively. The receptor for
haemagglutinin is the terminal sialic acid residue of host cell surface sialyloligosaccharides,
while sialidase catalyses the hydrolysis of terminal sialic acid residues from
sialyloligosaccharides. Extensive crystallographic studies of both these
proteins have revealed that the residues that interact with the sialic acid are
strictly conserved. Therefore, these proteins make attractive targets for the
design of drugs to halt the progression of the virus. Recent successful efforts
in the search for new cures for influenza have led to the development of three
clinically-useful anti-influenza drugs. All three are potent, selective
inhibitors of influenza virus A and B sialidase. Strategies for the development
of haemagglutinin inhibitors have also been devised.
[Back to top] Nuclear Import
of the Pre-Integration Complex (PIC): The Achilles Heel of HIV ?
S.
C. Piller1, L. Caly , and D. A.
Jans
Current treatments
against the Aquired immune deficiency syndrome (AIDS) are reasonably effective
in reducing the amount of human immunodeficiency virus (HIV) present in
infected patients, but their side-effects, and the emergence of drug-resistant
HIV strains have intensified the renewed search for novel anti-HIV therapies.
An essential step in HIV infection is the integration of the viral genome into
the host cell chromosomes within the nucleus. Unlike other retroviruses, HIV
can transport its genetic material, in the form of the large nucleoprotein
pre-integration complex (PIC), into the nucleus through the intact nuclear
envelope (NE). This enables HIV to infect non-dividing cells such as
macrophages and microglial cells. Detailed knowledge of the signal-dependent
pathways by which cellular proteins and RNAs cross the NE has accumulated in
the past decade, but although several different components of the PIC have been
implicated in its nuclear import, the mechanism of nuclear entry remains
unclear. Since specifically inhibiting PIC nuclear import would undoubtedly
block HIV infection in non-dividing cells, this critical step of HIV replication
is of great interest as a drug target. This review examines the complex and
controversial literature regarding three PIC components – the HIV proteins
matrix, integrase and Vpr – proposed to facilitate PIC nuclear import, and
existing models of HIV PIC nuclear import. It also suggests approaches to move
towards a better understanding of PIC nuclear import, through examining the
role of individual PIC components in the context of the intact PIC by direct
visualisation, in order to develop new anti-HIV therapeutics.
[Back to top] Virally Encoded G Protein-Coupled Receptors:
Targets for Potentially Innovative Anti-Viral Drug Development
Smit,
M.J. , Vink, C. , Verzijl, D., Casarosa, P.,
Various herpes- and poxviruses contain DNA sequences encoding proteins with homology to cellular chemokine receptors, which belong to the family of G protein-coupled receptors (GPCRs). Since GPCRs play a crucial role in cellular communication and chemokine receptors play a prominent role in the immune system, the virally encoded GPCRs may be crucial determinants of viral action. The Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus 8), implicated in the pathogenesis of Kaposi's sarcoma (KS), a highly vascularized tumor, encodes a GPCR, referred to as ORF74. This virally encoded receptor was found to induce tumorigenesis and transgenic expression of ORF74 induces an angioproliferative disease resembling KS. Cytomegalovirus (CMV), suggested to play a role in atherosclerosis, encodes four GPCRs, among which US28. This virally encoded GPCR is able to induce migration of smooth muscle cells, a feature essential for the development of atherosclerosis. Remarkably, the KSHV and some CMVencoded GPCRs display constitutive activity, while their cellular homologs do not. It remains to be determined whether this phenomenon contributes to the pathogenesis of viral action. Also, the family of poxviruses encodes GPCRs of which the function is not clear yet. In this review we will give an overview of the different virally encoded GPCRs, and discuss their putative role in viral action and potential as drug target.