Current Pharmaceutical Design, Volume 10, No. 32, 2004
Contents
Anti-HIV
Drug Design and Therapy
Executive
Editor: Ted M. Ross
Anti-HIV Drug Development – An Overview Pp.4005-4037
Candida F. Pereira and Judith T.M.L. Paridaen
Action of Anti-HIV Drugs and Resistance:
Reverse Transcriptase Inhibitors and Protease Inhibitors Pp. 4039-4053
Tomozumi
Imamichi
Acquisition of Multi-PI (Protease Inhibitor)
Resistance in HIV-1 In Vivo and In Vitro Pp. 4055-4064
Keisuke
Yusa and Shinji Harada
Drug Resistance, Virus Fitness and HIV-1
Mutagenesis Pp. 4065-4070
Renxiang
Chen, Miguel E. Quinones-Mateu and Louis M. Mansky
Antiretroviral Drugs and The Kidney: Dosage
Adjustment and Renal Tolerance Pp.
4071-4079
Hassane
Izzedine, Vincent Launay-Vacher and Gilbert Deray
Antiviral Drugs that Target Cellular Proteins
May Play Major Roles in Combating HIV Resistance Pp. 4081-4101
Veronic
Marie Isabelle Provencher, Ersilia Coccaro, Jonathan Jacques Lacasse and Luis
Maria Schang
“Virostatics” as a Potential New Class of HIV
Drugs Pp. 4103-4120
L.
M. Kelly, J. Lisziewicz and F. Lori
Cellular Physiology of Mismatch Repair Pp. 4121-4126
X.
Wu, Z. Khalpey and M. Cascalho
Current Biological Therapies for Inflammatory
Bowel Disease Pp.4127-4147
Daniel
C. Baumgart and Axel U. Dignass
Abstracts
[Back to top] Anti-HIV Drug Development – An Overview
Cândida
F. Pereira and Judith T.M.L. Paridaen
Highly active antiretroviral therapy (HAART)
has markedly decreased mortality and morbidity in the developed world. HAART
consists of a combination of three or more of the following classes of
antiretroviral (ARV) drug: reverse transcriptase inhibitors, protease
inhibitors and a recently approved fusion inhibitor. However, HAART cannot
completely eradicate HIV from the body, results in long-term toxicity and
eventually leads to the emergence of drug-resistant HIV strains. These problems
prompt the search for potent new drugs that are active against drug-resistant
viral strains and that can safely be combined with other ARV drugs. The aim of
this review was to give an overview of new compounds in preclinical or early clinical
development that interact with various steps in the HIV life cycle: viruscell
attachment; gp120-CD4 binding; gp120-coreceptor binding; viral fusion; viral
assembly and disassembly; reverse transcription; nuclear import of the
pre-integration complex; proviral integration; viral transcription; processing
of viral transcripts and nuclear export; assembly of new virions; cellular
factors involved in HIV replication.
[Back to top] Action of Anti-HIV Drugs and Resistance: Reverse
Transcriptase Inhibitors and Protease Inhibitors
Tomozumi
Imamichi
Currently, 20 drugs have been approved for
Human Immunodeficiency Virus type-1 (HIV-1) clinical therapy. These drugs
inhibit HIV-1 reverse transcriptase, protease, or virus entry. Introduction of
a combination therapy with reverse transcriptase inhibitors and protease
inhibitors has resulted in a drastic decrease in HIV-1 related mortality.
Although the combination therapy can suppress viral replication below detection
levels in current available assays, low levels of on-going viral replication
still persist in some patients. Long-term administration of the combination
therapy may increase selective pressure against viruses, and subsequently
induce emergence of multiple drug-resistant HIV-1 variants. Attempts have been
made to design novel antiretroviral drugs that would be able to suppress
replication of the resistant variants. At present, several investigational
drugs are being tested in clinical trials. These drugs target not only the
resistant variants, but also improvement in oral bioavilability or other viral
proteins such as HIV-1 integrase, ribonuclease H, and HIV-1 entry (CD4
attachment inhibitors, chemokine receptors antagonists, and fusion inhibitors).
Understanding mechanism(s) of action of the drugs and mechanisms of drug
resistance is necessary for successful designs in the next generation of
anti-HIV-1 drugs. In this review, the mechanisms of action of reverse
transcriptase- and protease-inhibitors, and the mechanism of resistance to
these inhibitors, are described.
[Back to top] Acquisition of Multi-PI (Protease Inhibitor)
Resistance in HIV-1 In Vivo and In Vitro
Keisuke
Yusa and Shinji Harada
Protease inhibitors are effective antiviral
agents which can lead to a severe decrease in HIV RNA copies in plasma of naďve
patients, however even successful suppression of the virus with antiretroviral
agents including protease inhibitor(s) (PI(s)) generates PI-resistant HIV-1
after long term treatment. Occasionally HIV-1 acquires cross-resistance to
other PIs with which the patients have not been treated. Cross-resistance to
multiple PIs (multi-PI resistance) leads to a restricted salvage strategy;
therefore multi-PI resistance is one of the serious obstacles to efficient
antiretroviral chemotherapy. The most common PI-resistance mechanism in HIV-1
is the emergence and accumulation of multiple amino acid substitutions within
the viral protease. As well, additional substitutions in protease cleavage sites
or substitutions in the Gag protein at non-cleavage sites are involved in
recovery of the reduced replication fitness of HIV-1 caused by these mutations
in the viral protease. To address or predict the resistance mechanisms of PIs,
resistant HIV-1 variants have been intensively studied in vitro.
However, the profiles of the amino acid substitutions obtained in PI resistant
variants are more diverse and complex than that found in vitro. More
elaborate in vitro systems for further analysis of acquisition of PI
resistance mechanisms are needed.
[Back to top] Drug Resistance, Virus Fitness and HIV-1
Mutagenesis
Renxiang
Chen, Miguel E. Quinones-Mateu and Louis M. Mansky
The evolution of
antiretroviral drug resistance is a major problem in the treatment of human
immunodeficiency virus type 1 (HIV-1) infection. Drug therapy failure is
associated with accumulation of drug resistance mutations and results in the
development of drug resistance. Drugs targeted against reverse transcriptase
(RT) as well as drug-resistant RT have been shown to increase HIV-1 mutation
frequencies. Furthermore, combinations of drug and drug-resistant RT can
increase virus mutation frequencies in a multiplicative manner. The evolution
of drug resistance also alters virus fitness. The correlation of increased
HIV-1 mutation rates with the evolution of antiretroviral drug resistance
indicates that drug failure could increase the likelihood of further resistance
evolving from subsequent drug regimens. These observations parallel studies
from microbial systems that provide evidence for a correlation between drug
resistance development and increased pathogen mutation rates. Although
increased mutant frequencies may be detrimental to effective therapy, the
lethal mutagenesis of the HIV-1 genome may provide a new means for
antiretroviral therapy.
[Back to top] Antiretroviral Drugs and The Kidney: Dosage
Adjustment and Renal Tolerance
Hassane
Izzedine, Vincent Launay-Vacher and Gilbert Deray
Background. Acquired immunodeficiency
syndrome (AIDS)-related kidney disorders concern 30% of those patients and can
lead to end-stage renal disease (ESRD; 0.6 to 1%). Therefore, administration of
antiretroviral drugs in human immunodeficiency virus (HIV) patients with
nephropathy is not uncommon.
Aim of the review. Since renal insufficiency
is not uncommon among HIV-infected patients treated with antiretroviral drugs,
guidelines on how to use these drugs in the pattern of an altered renal
function are mandatory. This review provides such guidelines established on the
basis of pharmacokinetic and clinical studies reported in the international
literature. In addition, some of these drugs may be nephrotoxic. Mechanisms and
clinical and/or biological manifestations are reviewed to help monitor renal
tolerance in patients receiving these drugs.
Conclusion. Antiretroviral drugs’ dosage in HIV-infected patients with altered
renal function should be cautiously determined. Drug dosage should not be
systematically reduced since dosage adjustment is not mandatory for all
therapies (ie. protease inhibitors). Furthermore, when dose reduction is
necessary, pharmacokinetic and clinical data from the literature allows to establish
practical guidelines on how to use these drugs in such patients.
[Back to top] Antiviral Drugs that Target Cellular Proteins May Play Major Roles in
Combating HIV Resistance
Veronic
Marie Isabelle Provencher, Ersilia Coccaro, Jonathan Jacques Lacasse and Luis
Maria Schang
Despite the significant progresses made in
antiretroviral therapy, current drugs still cannot cure or prevent HIV
infection. And all drugs continue to select for drug-resistant HIV strains.
Consequently, new antiretroviral drugs are constantly being developed. To
ensure safety, these drugs are usually designed to inhibit viral proteins. But
cellular proteins are also emerging as potential targets for new antiretroviral
drugs. Two drugs that target cellular proteins inhibit HIV replication in
vitro, hydroxyurea (HU) and pharmacological cyclin-dependent kinase
inhibitors (PCIs). HU has been tested in clinical trials, commonly in
combination therapies. PCIs, which are newer drugs, have just started to be
tested in animal models of HIV-induced disease.
Herein, we will review the HIV replication
cycle and discuss the biological causes why strains resistant to antiviral
drugs are so easily selected for. We will then discuss current antiretroviral
drugs and HU before focusing on PCIs. PCIs have demonstrated to be effective
against wild-type and drug-resistant strains of HIV in vitro, while
selecting for no drug resistance. PCIs are additive with conventional antiviral
drugs against herpes simplex virus, which suggests that they could also be
additive with antiretroviral drugs. Since PCIs are proving surprisingly safe in
human clinical trials (against cancer), they may be developed as clinical
antiretroviral drugs in the near future. Recent and exciting studies indicate
that PCIs ameliorate the pathogenesis of an animal model of HIV-induced
nephropathy. We can expect that the full potential of PCIs as antiretroviral
drugs will be explored in the coming years.
[Back to top] “Virostatics” as a Potential New Class of HIV Drugs
L.
M. Kelly, J. Lisziewicz and F. Lori
The combination of three or more
antiretroviral drugs is referred to as highly active antiretroviral therapy
(HAART) and constitutes the standard of care for HIV-1 patients in
industrialized nations. Although HAART is usually effective in reducing viral
load and re-constituting CD4 counts, latent virus reservoirs persist, and as
many as 60 years therapy [1, 2] may be required to eradicate the virus.
Meanwhile, patients are likely to experience drug related toxicity and may have
to change therapy due to the emergence of drug resistant strains. For these
reasons, the search for different therapeutic approaches continues. A new
concept of antiviral/cytostatic (“virostatics”) drugs has been proposed within
the context of HAART to restrict virus target populations (CD4+ T
lymphocytes), target viral reservoirs, and possibly restore immune functions,
by reducing excess immune activation, a fundamental component of HIV/AIDS
pathogenesis. These virostatics include drugs such as hydroxyurea, mycophenolic
acid, leflunomide and rapamycin, which are currently used for other therapeutic
indications; and other experimental drugs, which are not for human use. They
utilize multiple novel mechanisms of action to impede HIV by targeting host
cellular proteins that are not susceptible to mutation. Therefore, their
resistance profile appears to be quite favorable. Since many of these drugs act
by inhibiting the synthesis of deoxynucleotides, essential for HIV reverse
transcription, they favor the incorporation of nucleoside analogues into viral
DNA, thus synergizing with the antiviral activity of currently used nucleoside
reverse transcriptase inhibitors (NRTI). The rationale for the use of
virostatics in HIV/AIDS, their mechanism of action, and ongoing preclinical and
clinical research will be reviewed.
[Back to top] Cellular Physiology of Mismatch Repair
X.
Wu, Z. Khalpey and M. Cascalho
The DNA mismatch repair system maintains
genomic stability by correcting DNA sequence errors generated during DNA
replication, during genetic exchanges between chromosomes i.e., recombination,
and by correcting DNA lesions caused by mutagenic agents such as cis-platinum.
Post-synthesis mismatch repair improves almost 1000-fold the fidelity of DNA
replication; however, the functions of mismatch repair proteins extend well
beyond DNA repair. Recent studies suggest that mismatch repair is part of the machinery
that couples DNA damage and repair to cell cycle regulation and apoptosis.
These studies indicate that tolerance to certain DNA lesions (such as
methylation and cis-platinum adducts) is associated with inefficient activation
of cell cycle checkpoints and inefficient activation of apoptosis in mismatch
repair deficient cells. Hence, mismatch repair proteins regulate the survival
threshold to DNA damage, and this function provides a novel platform for
understanding the role of mismatch repair in B cells, in tumor formation, as
well as in resistance to chemotherapy. In this communication, we review how
mismatch repair may contribute to the physiology of cells and may be regulated
by the intracellular trafficking of mismatch repair proteins.
[Back to top] Current Biological Therapies for Inflammatory Bowel Disease
Daniel
C. Baumgart and Axel U. Dignass
Current biological therapies for inflammatory
bowel disease reflect the exponential advancement in understanding the human
intestinal immune system and particularly the biology of intestinal
inflammation over the past decade. The better understanding of the mechanisms
of inflammatory bowel disease has evolved from descriptive clinical data and
genetically engineered animal models. It led to great interest in a variety of
new therapeutic agents and procedures with novel actions.
This review will discuss the mechanisms of
biologics (antibodies against pro-inflammatory cytokines, T-cell antibodies,
anti-inflammatory cytokines, adhesion molecule blockers, growth factors, colony
stimulating factors, fusion proteins, antisense oligonucleotides, hormones,
immunostimulatory DNA (ISS-DNA, CpG Oligodeoxynucleotides) and parasites (Trichuris
suis eggs), used in inflammatory bowel disease and summarize the available
data on investigational and approved agents, and briefly touch on probiotics
and extracorporeal immunomodulation (leukocyte apheresis and photoapheresis).
Based on the data discussed, it appears that
biologics may play an increasing role in managing inflammatory bowel disease in
the near future.