Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 9, 2006
Contents
Nucleotides and Nucleosides
Guest Editor: Dr. Li-he Zhang
Editorial Pp. 849
Nucleoside Analogs as Anti-HBV Agents Pp. 851-865
Xiao-Xiong Zhou and Eddy Littler
[Abstract]
Progress in 7-Deazapurine - Pyrrolo[2,3-d]pyrimidine
–Ribonucleoside Synthesis Pp. 867-892
Frank Seela and Xiaohua Peng
[Abstract]
RNA Interference with Chemically Modified siRNA Pp.
893-900
Hong-Yan Zhang, Quan Du, Claes Wahlestedt and Zicai Liang
[Abstract]
RNA Interference and Potential Applications
Pp. 901-911
Demin Zhou, Qiuchen S. He, Cuiying Wang, Jing Zhang and Flossie
Wong-Staal
[Abstract]
Chemical and Structural Diversity of siRNA Molecules
Pp. 913-925
Barbara Nawrot and Katarzyna Sipa
[Abstract]
Abstracts
[Back to top]
Editorial
Over the last decade, small molecule nucleoside and nucleotide
drugs have attracted much attention due to a remarkable increase
for the treatment of viral diseases. Currently more than 20
drugs fall into this category. Nucleoside antiviral drugs
are pro-drugs in that they are actively transpored into cells
and then activated by cellular kinases to the nucleotide triphosphate
(NTP). This NTP is now able to competitively inhibit the enzyme
or, more commonly, act as a substrate and be incorporated
into the growing polynucleotide chain subsequently prevents
(chain-terminates) the further replication of the viral genome.
Extensive research efforts have been directed toward the development
of nucleoside therapeutics, structural modified nucleoside
inhibitors can vary in either (or both) the ribose or base
portion of the molecule. In this issue, two chapters describe
the development of anti-HBV nucleosides and the chemistry
of 7-deazapurine ribonucleosides.
RNA interference (RNAi) is a new field to describe the use
of small inhibitory double-stranded RNA (siRNA) to target
for degradation sequence-specific cellular mRNAs, and as a
result to silencing gene expression. With the more recent
development of RNAi in mammalian systems, investigators are
not only dissecting gene function but also attempting the
development of new therapeutic approaches in human genetics
and/or infectious diseases. The main challenge for translating
the experimental success of siRNA into clinical applications
is how to solve the problems of the stability of siRNA in
blood and the delivery to target. Three research groups are
invited to review the recent developments in this area.
Thanks to Current Topics of Medicinal Chemistry for
this special issue which makes us to share these very interesting
topics.
Prof. Li-He Zhang
State Key Laboratory of Natural
& Biomimetic Drugs
School of Pharmaceutical Sciences
Peking University
Beijing 100083,
China
E-mail: zdszlh@bjmu.edu.cn
[Back to top]
Nucleoside Analogs as Anti-HBV Agents
Xiao-Xiong Zhou and Eddy Littler
Chronic hepatitis B virus (HBV) infection affects about 400
million people worldwide. The development of nucleoside analogs
that inhibit HBV polymerase provides an important approach
for treating HBV infection. The approval of lamivudine, adefovir
and entecavir represents a cornerstone of hepatitis B therapy.
However, the challenges from the resistance and the off-therapy
viral rebound are still unmet, and there is a need of developing
new therapeutic agents. This review will discuss the structure-activity
relationship of the most significant anti-HBV nucleoside analogs
and the latest development in the field.
[Back to top]
Progress in 7-Deazapurine - Pyrrolo[2,3-d]pyrimidine
–Ribonucleoside Synthesis
Frank Seela and Xiaohua Peng
This review reports on the synthesis of 7-deazapurine ribonucleosides,
including C-nucleosides, 2'-C-methyl derivatives and L-enantiomers.
It covers the various aspects of convergent nucleoside synthesis
such as the Schiff base procedure, the fusion reaction, the
metal salt procedures, the Silyl-Hilbert-Johnson reaction,
and the nucleobase anion glycosylation. The review discusses
the scope and limitations of glycosylation reactions performed
on 7-deazapurines. Peracylated ribose derivatives were now
employed in the glycosylation, which overcome difficulties
reported earlier.
[Back to top]
RNA Interference with Chemically Modified siRNA
Hong-Yan Zhang, Quan Du, Claes Wahlestedt and Zicai Liang
siRNA has become an indispensable tool for functional characterization
of genes. It has also demonstrated tremendous potential as
a new generation of drug candidates. Although the technology
works very well to a great panel of cells in vitro,
it is still a challenge to translate the success into in
vivo target validation easiness and, even more difficult,
into therapeutic applications. With a number of chemically
modified compounds under initial clinical trial from several
commercial entities, the interests in chemical modification
of siRNA have become heightened. In this review we have tried
to touch on most of the chemical modifications of RNA that
have been tested in the siRNA landscape, but maintained a
focus on the backbone modifications, and 2’-modifications
on the ribose ring. It is anticipated that more modifications
and more systematic comparisons between different modifications
will be performed to draw more educated conclusions over some
of the modifications.
[Back to top]
RNA Interference and Potential Applications
Demin Zhou, Qiuchen S. He, Cuiying Wang, Jing Zhang and Flossie
Wong-Staal
RNA interference (RNAi) is the process of using specific
sequences of double-stranded RNA (dsRNA) to knock down the
expression level of sequence-homologous genes. Such ability
of small interfering RNA (siRNA) in mammalian cells will undoubtedly
revolutionize the study of functional genomics, the discovery
of drug targets and even the treatment of human diseases.
In this review we briefly describe the history of RNAi discovery,
the RNAi mechanism and the general guideline for siRNA design
as well as various methods for siRNA production and delivery.
We also introduce the potential applications of siRNA, inducible
siRNA and siRNA library in speeding up basic biomedical research
and in acting as potential therapeutic agents for treatment
of numerous human diseases.
[Back to top]
Chemical and Structural Diversity of siRNA Molecules
Barbara Nawrot and Katarzyna Sipa
Short interfering RNAs (siRNAs) are 21-23 nt long double-stranded
oligoribonucleotides which in mammalian cells exhibit a potency
for sequence-specific gene silencing via an RNA interference
(RNAi) pathway. It has been already proven that exogenous,
chemically synthesized siRNA molecules are effective inhibitors
of gene expression and are widely applied for analysis of
protein function and proteomics-based target identification.
Moreover, since their discovery siRNA molecules have been
implemented as potential candidates for therapeutic applications.
Variously modified siRNA molecules containing sugar modifications
(2’-OMe, -F, -O-allyl, -amino, orthoesters and LNA analogues),
internucleotide phospodiester bond modifications (phosphorothioates,
boranophosphates), base modifications (s2U) as well as 3’-terminal
cholesterol-conjugated constructs were investigated as potential
candidates for effective inhibition of gene expression. This
chapter reviews an impact of chemical and structural modifications
of siRNA molecules on their serum and thermal stability, cellular
and in vivo activity, cellular uptake, biodistribution
and cytotoxicity. Functional analysis of chemically modified
siRNA molecules allows for better understanding of the mechanism
of the RNA interference process as well as demonstrates immense
efforts in optimizing in vivo potency of siRNA molecules
for RNAi-based drug design.
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