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Infectious Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')
ISSN: 1871-5265
Current Drug Targets - Infectious
Disorders
Volume 5, Number 4, December 2005
Contents
Developments in Antiviral Drug Design, Discovery and Development
in 2004 Pp.307
Nicholas A. Meanwell, Makonen Belema, David J. Carini,
Stanley V. D’Andrea, John F. Kadow, Mark Krystal, B.
Narasimhulu Naidu, Alicia Regueiro-Ren, Paul M. Scola, Sing-Yuen
Sit, Michael A. Walker, Tao Wang and Kap-Sun Yeung
[Abstract]
Neuraminidase Inhibitors as Antiviral Agents Pp.401
I.V. Alymova, G. Taylor and A. Portner
[Abstract]
Chemosensitizers in Drug Transport Mechanisms Involved
in Protozoan Resistance Pp.411
Bruno Pradines, Jean-Marie Pagès and Jacques Barbe
[Abstract]
Discoveries of Tat-TAR Interaction Inhibitors for
HIV-1 Pp.433
Ming Yang
[Abstract]
Abstracts
[Back to top]
Developments in Antiviral Drug Design, Discovery and Development
in 2004
Nicholas A. Meanwell, Makonen Belema, David J. Carini,
Stanley V. D’Andrea, John F. Kadow, Mark Krystal, B.
Narasimhulu Naidu, Alicia Regueiro-Ren, Paul M. Scola, Sing-Yuen
Sit, Michael A. Walker, Tao Wang and Kap-Sun Yeung
This article summarizes key aspects of progress made during
2004 toward the design, discovery and development of antiviral
agents for clinical use. Important developments in the identification,
characterization and clinical utility of inhibitors of human
immunodeficiency virus; the hepatitis viruses, hepatitis B,
hepatitis C; the herpes family of viruses, herpes simplex
viruses 1 and 2, varicella zoster virus, Epstein-Barr virus
and human cytomegalovirus; the respiratory viruses, influenza,
respiratory syncytial virus, human metapneumovirus, picornaviruses,
measles and the severe acute respiratory syndrome coronavirus;
human papilloma virus; rotavirus; Ebola virus and West Nile
virus, are reviewed.
[Back to top]
Neuraminidase Inhibitors as Antiviral Agents
I.V. Alymova, G. Taylor and A. Portner
The enzyme neuraminidase (NA) is an attractive target for
antiviral strategy because of its essential role in the pathogenicity
of many respiratory viruses. NA removes sialic acid from the
surface of infected cells and virus particles, thereby preventing
viral self-aggregation and promoting efficient viral spread;
NA also plays a role in the initial penetration of the mucosal
lining of the respiratory tract. Random screening for inhibitors
has identified only low-affinity and nonselective viral NA
inhibitors. Selective, high-affinity inhibitors of influenza
virus neuraminidase, zanamivir and oseltamivir, were developed
using computer-aided design techniques on the basis of the
three-dimensional structure of the influenza virus NA. These
drugs were highly efficient in inhibiting replication of both
influenza A and B viruses in vitro and in vivo
and were approved for human use in 1999. Subsequently, the
same structure-based design approach was used for the rational
design of inhibitors of the parainfluenza virus hemagglutinin-neuraminidase
(HN). One of these compounds, BCX 2798, effectively inhibited
NA activity, cell binding, and growth of parainfluenza viruses
in tissue culture and in the lungs of infected mice. Clinical
reports indicate high efficiency of NA inhibitors for prophylaxis
and treatment of influenza virus infection, good tolerance,
and a low rate of emergence of drug-resistant mutants. Future
experimental and clinical studies should establish the viability
of NA inhibitors for the treatment of other respiratory virus
infections.
[Back to top]
Chemosensitizers in Drug Transport Mechanisms Involved
in Protozoan Resistance
Bruno Pradines, Jean-Marie Pagès and Jacques
Barbe
The emergence and spread of antiparasitic drug resistance
pose a severe and increasing public health threat. Failures
in prophylaxis or those in treatment with quinolines, hydroxynaphtoquinones,
sesquiterpenic lactones, antifolate drugs, arsenic and antimony
containing drugs sulfamides induce reemergence of parasitic-related
morbidity and mortality.
Resistance is often associated with alteration of drug accumulation
into parasites, which results from a reduced uptake of the
drug, an increased efflux or, a combination of the two processes.
Resistance to quinolines, artemisinin derivatives and arsenicals
and expression of an active efflux mechanism are more or less
correlated in protozoa like Plasmodium spp., Leishmania
spp., and Trypanosoma spp. Various parasite
candidate genes have been proposed to be involved in drug
resistance, each concerned in membrane transport. Genes encoding
membrane glycoproteins, orthologue to the P-glycoproteins
identified in MDR human cancer cells, have been described
in these resistant pathogens in addition to various membrane
proteins involved in drug transport.
Several compounds have demonstrated, in the past decade,
promising capability to reverse the drug resistance in parasite
isolates in vitro, in animal models and for human
malaria. These drugs belong to different pharmacological classes
such as calcium channel blockers, tricyclic antidepressants,
antipsychotic calmodulin antagonists, histamine H1-receptor
antagonists, analgesic antipyretic drugs, non-steroidal anti-inflammatory
drugs, and to different chemical classes such as synthetic
surfactants, alkaloids from plants used in traditional medicine,
pyrrolidinoaminoalkanes and derivatives, and anthracene derivatives.
Here, are summarized the molecular bases of antiparasitic
resistance emphasizing recent developments with compounds
acting on trans-membrane proteins involved in drug efflux
or uptake.
[Back to top]
Discoveries of Tat-TAR Interaction Inhibitors for
HIV-1
Ming Yang
A major problem associated with anti-HIV-1 treatment is rapid
emergence of drug-resistant strains. Accordingly, a compelling
need is to discover anti-HIV drugs against alternative viral
targets in addition to HIV-1 RT, PR, IN and CCR5. One such
target is the interaction between HIV Trans-activator of transcription
(Tat) protein and Trans Activation Responsive region (TAR)
RNA. An arginine-rich motif (ARM) of Tat recognizing both
the base sequence and the active conformation of TAR RNA three-base
bulge region as well as newly elucidated TAR RNA inactive
conformation are important for the specific Tat-TAR interaction.
According to the possible binding modes, the inhibitors have
been mainly divided into two classes: (1) Compounds binding
directly to TAR RNA either to the TAR RNA three-base bulge
region alone or to the three-base bulge together with the
lower and upper-stem/Loop region. (2) Compounds binding directly
to Tat protein with high affinity, thus potently inhibiting
HIV-1. They both block Tat trans-activation in the formation
of the Tat/TAR complex to exert antiviral activity in primary
human cells. Recent researches also focus on the drugs targeting
specificity of Tat and TAR by such new assays as capillary
electrophoresis and quartz crystal microbalance. Cell-based
reporter systems are established for high-throughput screening
of novel compounds that interfere with Tat transactivation.
The identification of dominant-negative mutants also finds
wide application in this field. The Tat-TAR interaction is
an important target in efforts to develop anti-HIV gene therapy
or potential therapeutic antiviral agents for the treatment
of HIV-1 infections.
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