Letters in Drug Design & Discovery, Volume 2, No. 2, 2005
Contents
Inhibition of Human Melanoma Cell
Replication Using Protein Transduction Technology with a Uracil-DNA Glycosylase
Inhibitor Pp.92-96
Maria E. Ariza, Irene Pedersen and M.V. Williams
Mitotic Checkpoint: A Therapeutic
Target in the Treatment of Human Cancer Pp.97-104
Xianghong Wang, Y.C. Wong and Dong-Yan Jin
The Application of Angiotensin
Converting Enzyme Inhibitors in Heart Surgery Pp.105-108
Yasuyuki Shimada
Inhibition of BACE-1 by Hydroxyethylsulfide,
Hydroxyethylamine and Hydroxyethylurea Isosteric Replacements Pp.109-112
L. Rizzi and S. Romeo
The Role of an Amphiphilic
Capping Group in Covalent and Non-Covalent Dipeptide Inhibitors of HCV NS3
Serine Protease Pp.113-117
Stefania Colarusso, Benjamin Gerlach, Claudio Giuliano, Uwe
Koch, Victor G. Matassa and Frank Narjes
P1 and P1’ Optimization of
[3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl a-Ketoamide Based HCV Protease
Inhibitors Pp.118-123
Shu-Hui Chen, Jason Lamar, Yvonne Yip, Frantz Victor,
Robert B. Johnson, Q. May Wang, John I. Glass, Beverly Heinz, Joseph Colacino,
Deqi Guo, Mark Tebbe and John E. Munroe
Avidin Fusion Protein Strategies
in Targeted Drug and Gene Delivery Pp.124-132
Olli H. Laitinen, Kari J. Airenne, Jani K. Raty, Thomas
Wirth and Seppo Yla-Herttuala
Synthesis and In Vitro
Evaluation of Adenosine Deaminase Resistant N-6 Aminal and Thioaminal
Prodrugs of Cordycepin Pp.133-136
Hui-Min Chang, Jesse Oakes, Anders Olsson, Luminita
Panaitescu, B. Mark Britt, Christopher M. Kearney and Robert R. Kane
Recognition of Specific DNA
Sequences by Stacked Pyrrole- and Imidazole- Containing Polyamides: An
Efficient Screening Method Based on Competitive Dialysis Pp.137-142
Karen L. Buchmueller, Sarah M. Horick, Cameron M. Howard,
Peter B. Uthe, Andrew M. Staples, Suzanna L. Bailey, N. Minh Le, Kari K. Cox,
James A. Henry and Moses Lee
Neuroprotection in Huntington’s
Disease Pp.143-147
Raphael M. Bonelli, Anna K. Hodl and Hans-Peter Kapfhammer
Biodegradable Additives Modulate
Ganciclovir Release Rate From PLGA Microspheres Destined to Intraocular Administration
Pp.148-149
Emilia Barcia, Cristina Herradon and Rocio Herrero-Vanrell
Anti-Viral Therapies for
Hepatitis C Virus Infection: Current Options and Evolving Candidate Drugs Pp.150-161
Liam J. Fanning
Activity of Amidine-containing
Diphenylureas Against P. falciparum Pp.162-164
Guatam Bhattacharya, Lucia Gerena, Suping Jiang and Karl A.
Werbovetz
Tamarind Inhibits Solar-Simulated
Ultraviolet Radiation-Induced Suppression of Recall Responses in Humans Pp.165-171
J.M. Kuchel, R.St.C. Barnetson, L. Zhuang, F.M. Strickland,
R.P. Pelley and G.M. Halliday
Abstracts
[Back to top] Inhibition of Human Melanoma Cell
Replication Using Protein Transduction Technology with a Uracil-DNA Glycosylase
Inhibitor
Maria E. Ariza, Irene Pedersen and M.V. Williams
We demonstrated that the uracil-DNA glycosylase inhibitor, when
delivered to human melanoma cells using protein transduction technology,
resulted in a dose and time dependent inhibition of uracil-DNA glycosylase
(UNG) and this inhibited cell proliferation. These results suggest that a novel
class of inhibitors specifically targeting UNG can be developed as potential
anti-cancer agents.
[Back to top] Mitotic Checkpoint: A Therapeutic
Target in the Treatment of Human Cancer
Xianghong Wang, Y.C. Wong and Dong-Yan Jin
The most common feature of human cancer cells is aneuploidy and a
defective mitotic checkpoint is thought to be responsible. Since a group of
anticancer drugs target the mitotic checkpoint, this review will discuss the
association of mitotic checkpoint with chemotherapeutic drug sensitivity and
suggest a novel therapeutic tool to achieve chemosensitization in human cancer
cells.
[Back to top] The Application of Angiotensin
Converting Enzyme Inhibitors in Heart Surgery
Yasuyuki Shimada
Animal and human studies have shown angiotensin converting enzyme (ACE)
inhibitors to be protective agents against myocardial injury, especially
ischemia/reperfusion injury. In this review of the application of ACE
inhibitors in heart surgery, I examine the problems involved and discuss their
solutions.
[Back to top] Inhibition of BACE-1 by
Hydroxyethylsulfide, Hydroxyethylamine and Hydroxyethylurea Isosteric
Replacements
L. Rizzi and S. Romeo
New inhibitors of the ß-site amyloid precursor protein cleaving enzyme
(BACE-1) are described. The hydroxyethyl transition state isostere of GT1017
has been replaced by the hydroxyethylamine (HEA), the hydroxyethylsulfide or
the hydroxyethylurea groups. Biological evaluation has shown that the HEA
analogue, obtained as epimeric mixture, inhibited BACE-1 with an IC50=0.12µM.
Stereoselective synthesis showed surprisingly that the most active stereoisomer
was the (R)-HEA transition state analogue with an IC50=0.014µM.
[Back to top] The Role of an Amphiphilic
Capping Group in Covalent and Non-Covalent Dipeptide Inhibitors of HCV NS3
Serine Protease
Stefania Colarusso, Benjamin
Gerlach, Claudio Giuliano, Uwe Koch, Victor G. Matassa and Frank Narjes
The analysis of the S3 binding region of the Hepatitis C Virus NS3
serine protease allowed replacing the P3 amino acid of a-ketoacid tripeptide
inhibitors with an amphiphilic capping group. The binding mode of a-ketoacid (8) (IC50 = 1 mM) and the role of the amphiphilic group in
non-covalent phenethylamide inhibitor (15) (IC50 = 21 mM) will be discussed.
[Back to top] P1 and P1’ Optimization of
[3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl a-Ketoamide Based HCV Protease
Inhibitors
Shu-Hui Chen, Jason Lamar,
Yvonne Yip, Frantz Victor, Robert B. Johnson, Q. May Wang, John I. Glass,
Beverly Heinz, Joseph Colacino, Deqi Guo, Mark Tebbe and John E. Munroe
We describe herein tetrapeptidyl a-ketoamide
4A based systematic P1 modifications alone or/and in combination with
further P1’ variations. These SAR efforts led to the discovery of a number of
potent and selective HCV NS3 protease inhibitors such as 4B, 9, and 12
endowed with impressive cellular activity as measured in the replicon assay and
very good therapeutic indexes. On the basis of its overall profile, compound 4B
(VX-950) has been selected for human clinical trials.
[Back to top] Avidin Fusion Protein Strategies in Targeted Drug and Gene
Delivery
Olli H. Laitinen, Kari J.
Airenne, Jani K. Raty, Thomas Wirth and Seppo Yla-Herttuala
Chicken avidin is used in a wide variety of applications in the life
sciences, due to its extraordinarily strong affinity for biotin. Avidin-biotin
strategy has also recently established a role in medical targeting approaches
for cancer treatments. An interesting new exploitation for avidin-biotin
techniques is the utilization of this strong affinity in gene therapy, to
target and enhance gene delivery to the appropriate target cells and tissues.
In this communication, we review novel avidin fusion proteins that have been
developed for enhanced gene delivery and drug targeting purposes. The
principles of this approach are highlighted by the avidin fusion proteins
Scavidin (fusion with the macrophage scavenger receptor class A), Lodavin
(fusion with the endocytotic LDL receptor) and avidin-displaying baculovirus
(Baavi). Scavidin and Lodavin are cell membrane proteins in which avidin is
expressed as an extracellular portion, thereby enhancing the targeted drug and
gene delivery with biotinylated drug molecules and vectors. Baavi, on the other
hand, displays avidin moieties on its surface, and opens up possibilities for
flexible modification of its targeting properties and other characteristics by
using different biotin-conjugated molecules. Potential applications of avidin
fusion proteins and future trends of targeted drug and gene delivery based on
these strategies will be discussed.
[Back to top] Synthesis and In Vitro Evaluation of Adenosine
Deaminase Resistant N-6 Aminal and Thioaminal Prodrugs of Cordycepin
Hui-Min Chang, Jesse Oakes,
Anders Olsson, Luminita Panaitescu, B. Mark Britt, Christopher M. Kearney and
Robert R. Kane
Cordycepin (3’-deoxyadenosine) is a potent anti-leukemic, anti-fungal,
and anti-parasitic nucleoside antibiotic. Unfortunately, the biological
activity of cordycepin is attenuated by its rapid conversion to 3’-deoxyinosine
by adenosine deaminase (ADA). We have synthesized a series of ADA-resistant N-aminal
and N-thioaminal cordycepin derivatives, which are protected from
inactivation by deamination and yet retain biological activity. These compounds
are hydrolyzed at various rates to efficiently release the parent drug
cordycepin, and likely serve as simple hydrolytically activated prodrugs.
[Back to top] Recognition of Specific DNA Sequences by Stacked Pyrrole-
and Imidazole- Containing Polyamides: An Efficient Screening Method Based on Competitive
Dialysis
Karen L. Buchmueller, Sarah M. Horick, Cameron M. Howard,
Peter B. Uthe, Andrew M. Staples, Suzanna L. Bailey, N. Minh Le, Kari K. Cox,
James A. Henry and Moses Lee
A competitive dialysis method has been developed to screen compounds for
their DNA binding properties, and it is based on directly comparing the binding
of polyamide molecules to a series of distinctively varied, short, synthetic
deoxyribonucleotides. Relative binding ratios for each polyamideoligonucleotide
pairing were calculated from the concentrations of free polyamide and total
polyamide in order to quantitatively compare binding to different DNA
sequences. This approach works well as a preliminary screen to determine the
viability of novel small molecules, prior to investing significant resources in
further characterization and development of possible sequence specific DNA
targeted therapeutic agents. The trends in binding affinities of the four
triamide molecules (f-ImPyIm, distamycin A, f-PyPyPy and f-ImImPy; where Im is
imidazole and Py is pyrrole) correlated well with data obtained from surface
plasmon resonance (SPR) studies. Results from circular dichroism studies
confirmed the minor groove side-by-side stacked binding motif of the triamides,
and thermal stability experiments corroborated the improved DNA stability of
promising polyamide-DNA complexes. The affinity of distamycin A for its cognate
DNA sequence (A3T3) was unambiguously selected over the
other DNA sequences tested. Alternatively, as expected from SPR, circular
dichroism and thermal melting experiments, f-ImImPy showed very poor affinity
for DNA sequences tested, including its cognate DNA, TCGA. Thus, the very good
(distamycin A) and very poor (f-ImImPy) DNA binders were effectively screened.
[Back to top] Neuroprotection in Huntington’s Disease
Raphael M. Bonelli, Anna K.
Hodl and Hans-Peter Kapfhammer
Minocycline, the 7-dimethylamino- 6-dimethyl-desoxytetracycline hydrochloride,
is a caspase-1 inhibitor and may serve as anti-apoptotic agent, thereby acting
neuroprotective. It directly inhibits both caspase-independent and -dependent
mitochondrial cell death pathways, and decreases inducible nitric oxide
synthetase activity. Minocycline delays disease progression in the transgenic
mouse model of Huntington’s disease (HD), extending survival by 14%. HD is a
late onset relentlessly progressive, neurodegenerative disorder with currently
no cures or even effective therapies, death occurring 15 years after onset. In
this review, recent clinical and preclinical data on minocycline in HD and
neuroprotective alternatives discussed.
[Back to top] Biodegradable Additives Modulate Ganciclovir Release Rate
From PLGA Microspheres Destined to Intraocular Administration
Emilia Barcia, Cristina
Herradon and Rocio Herrero-Vanrell
Human cytomegalovirus (HCMV) retinitis treated with frequent
intraocular injections of ganciclovir is associated with complications such as
endophthalmitis, retinal detachment and vitreous haemorrhage. Several
formulations of biodegradable injectable PLGA microspheres with ganciclovir
have been previously investigated as a possible alternative for treatment of
HCMV retinitis. This report describes two new formulations of PLGA microspheres
with ganciclovir that also include alpha tocopherol (vitamin E) or glyceryl
tricaprylate/caprate (miglyol) as additives, modulating the release rate of
ganciclovir. While additive free microspheres in vitro released about
90% of its ganciclovir within 20 days, the microspheres with the additives
released only 20% of the drug during this period, and continued releasing the
drug at the same rate for a total of 42 days.
[Back to top] Anti-Viral Therapies for Hepatitis C Virus Infection:
Current Options and Evolving Candidate Drugs
Liam J. Fanning
Chronic hepatitis
C is a ubiquitous disease, affecting approximately 170 million globally. The
hepatitis C virus (HCV) is spread by parenteral transmission of body fluids,
primarily blood or blood products. The hepatitis C viral genome is a
positive-sense, single-stranded RNA molecule approximately 9.4kb in length,
which encodes a polyprotein of about 3100 amino acids. There are 6 main
genotypes of HCV, with each further stratified by subtype. Hepatitis C virus
exists as a heterogeneous mixture of closely related viruses called
quasispecies. The continuous evolution of new variant glycoproteins is a major
mechanism of viral evasion of the immune system. The quasispecies diversity
collapses to oligoclonality or homogeneity prior to clearance. Substantial
evidence indicates that HCV genotype is clinically important with respect to
efficacy of anti-viral therapy. The dual drug regime currently used to treat
HCV infection consists of pegylated-interferon (peg-IFN) and the guanosine
nucleoside analog ribavirin. Mutations in the viral genome are likely to
contribute in large measure to the emergence of "resistance" during
interferon-based therapy.
The HCV genome
codes for 10 proteins. The structural proteins of core, E1, E2 and P7 are
positioned immediately downstream of the 5’UTR. These proteins are cleaved from
the polyprotein by host-encoded proteases. The remaining proteins are released
from the polyprotein by a process of autocatalytic cleavage or by the protease
activity of NS3. The RNA dependent RNA polymerase (NS5B) is position
immediately downstream of the 3’UTR. The current cytokine based treatment
modality is based on a shotgun approach of up regulation of cellular anti-viral
pathways. The net effect of IFN signalling is the down regulation of protein
translation. The cellular signalling pathways induced by IFN engagement of the
cognate receptor are not specific for the elimination of HCV. HCV has evolved
mechanisms that hinder IFN signalling and the induction of nuclease activity
that would otherwise destroy the viral genome. The net benefit to the virus is
that it potentiates the establishment of persistence.
The activity of the
host encoded proteases necessary for the cleavage of Core-P7, the proteolytic
activity of NS3, the helicase activity of NS3 and the polymerase activity of
NS5B are all potential targets for the development of adjunct options for the
treatment of hepatitis C virus infections. The development of novel antivirals
suitable for use against HCV has learnt a great deal from the research and
development of drugs used to treat HIV disease. Like HIV, HCV has the
propensity to produce greater than 1010 virions per day. Each genome
will have a fitness potential to survive each unique selection pressure
(endogenous and/or exogenous) and it is to be expected that again like HIV, HCV
will have the potential to evolve drug resistant mutants. The goal of highly
active antiretroviral therapy in HIV disease is viral suppression. However, it
would appear that elimination, rather than suppression of viral replication, in
HCV disease is achievable at least in a proportion of patients. The phenomenon
of quasispecies is likely responsible for the ineffectiveness of
isolate-specific vaccines and will challenge the development of pangenotype
antiviral therapies. New strategies based on antisense and ribozyme
technologies may hold future promise as therapeutic adjuncts in the treatment
of HCV infection.
[Back to top] Activity of Amidine-containing Diphenylureas Against P.
falciparum
Guatam Bhattacharya, Lucia Gerena, Suping Jiang and Karl A. Werbovetz
Amidine-containing derivatives of the diphenylurea antimalarial lead
compound WR268961, a putative plasmepsin inhibitor, were prepared and tested
against erythrocyte-stage P. falciparum. Diamidine 8 was the most active
compound, displaying IC50 values of 54 nM and 41 nM versus
chloroquine sensitive (D6) and chloroquine resistant (W2) parasites,
respectively.
[Back to top] Tamarind Inhibits Solar-Simulated Ultraviolet
Radiation-Induced Suppression of Recall Responses in Humans
J.M. Kuchel, R.St.C. Barnetson, L. Zhuang, F.M. Strickland,
R.P. Pelley and G.M. Halliday
To determine whether topically applied biologically active drugs can be
used to protect the human immune system from sunlight, we studied the effect of
tamarind xyloglucan polysaccharide, a natural and common fruit constituent, on
solar-simulated, ultraviolet radiation-induced local immunosuppression and
erythema in humans. Immunosuppression was studied in humans using a nickel
contact hypersensitivity recall model. Ultraviolet dose responses were
generated to determine the extent to which tamarind affected the immune
response in a group of 15 volunteers. The subsequent nickel-induced erythema
was quantitated using a reflectance spectrometer. 0.1 mgml-1 of
topical tamarind polysaccharide reduced ultraviolet radiation-induced
immunosuppression. Frozen sections of biopsies taken were analysed by
immunohistochemistry. Tamarind inhibited ultraviolet radiation-induced CD11c+
dendritic cell loss from the epidermis. The ultraviolet doses used in this
study did not alter the number of Mac387+ macrophages or NP57+ neutrophils
infiltrating the skin. Low dose xyloglucan polysaccharide from tamarind
protected from immunosuppression in humans, possibly by reducing ultraviolet
radiation-induced loss of dendritic cells, demonstrating that these types of
drugs may be useful adjuncts to sunscreens for protection from skin cancer.