Current Pharmaceutical Design - Volume 12, Issue 16, 2006

The need to discover novel means to treat HIV infection remains as critical as ever since the epidemic of AIDS continues to grow unabated. The emergence of resistant virus strains and the toxic side effects of current drugs require new classes of therapeutic agents with better and safer properties. In this issue of "Current Pharmaceutical Design" several authors review their effort of accomplishing this task. Debra Meyer proposes the use of iron chelators as a therapy for AIDS and tuberculosis (TB) since excess iron in the body assists to multiplication of causative pathogens [1]. Chelators in clinical use like desferioxamine, deferiprone, and bleomycin along with others still under development have been shown to inhibit HIV and mycobacterium in vitro. Concurrent infection with HIV and Mycobacterium tuberculosis is common, especially in developing countries, and thus if these chelators are found effective they could become treatment of choice as safe and effective therapy. Pohlmann and Reeves describe inhibitors of HIV entry as promising class of drug candidates [2]. The penetration of HIV into target cells involves interactions of the viral envelope protein (Env) with CD4 and a coreceptor, usually CCR5 or CXCR4. Both, virus receptors and structures in Env associated with membrane fusion are promising targets for therapeutic intervention. Pumfery et al., review inhibitors of cyclin-dependent kinases (CDKs) as key regulators of the cell cycle and RNA polymerase II transcription [3]. Pharmacological CDK inhibitors (PCI) are known as potential cancer therapeutic agents. However, lately they have been shown to display anti-viral activity against several types of viruses. HIV replication appears to be blocked through CDK2 and 9, and cellular co-factors for HIV-1 Tat transactivation. These authors explain inhibitory mechanisms of flavopiridol and CYC202 and discuss their possible use for AIDS therapy. Varier and Kundu bring up recent advances in our understanding of genome-integrated viral gene expression and show that the regulation of chromatin function is closely linked to the replication of HIV [4]. Therefore, they propose a new therapeutic approach by targeting the chromatin-modifying enzymes such as histone acetyltransferases and deacetylases that may lead to new anti-HIV therapeutics. Christopher and Wong discuss the important aspect of delivery of antiviral drugs [5]. Recently, nucleic acid-based drugs have shown promise as anti-viral agents but their therapeutic efficacy is often restricted by limited delivery to intracellular sites of viral replication and by nuclease degradation. Several candidate AIDS drugs from this class including antisense oligonucleotides, siRNAs, ribozymes and DNAzymes are now in development. These authors review their own and research by others on finding means to optimize drug delivery to the desired target cells while eliminating adverse side effects. Bregenholt et al., look at the treatment of HIV and other viral infections from viewpoint of therapeutic antibodies [6]. This type of therapy has become popular in recent years as first commercial antibody preparations became highly successful. They have developed a recombinant technology that allows to use polyclonal instead of monoclonal antibodies. Due to unique design, so-called symphobodies, can be employed against a variety of pathogenic viruses, including vaccinia, smallpox virus, respiratory syncytial virus, and HIV. Finally, Bourinbaiar et al., review therapeutic AIDS vaccines with special emphasis on vaccines which operate according to the principles of alloimmunization [7]. Unlike prophylactic vaccine designed to prevent HIV infection, therapeutic vaccine is given to infected individuals to help fight the disease by modulating their immune response. The results of over sixty therapeutic vaccine trials have consistently shown that while in vitro measured HIVspecific immune responses were evident as a result of vaccination no obvious clinical improvements have been observed. The instances of the apparent clinical benefit, however, were invariably associated with vaccines that contained allo- or auto-antigens. Examples of such vaccines are reviewed in detail. The current strategy in finding effective AIDS therapy needs to be supplemented by research on therapeutic antibodies and vaccines. Taken together, these articles provide a glimpse on the current drug discovery effort in AIDS arena. This information should be of particular interest to seasoned as well as to new investigators in HIV field and may aid in the conceptualization of various strategies aimed at managing this difficult-to-treat disease. 1942 Current Pharmaceutical Design, 2006, Vol. 12, No. 16 HIV Drug Design References [1] Meyer D. Iron chelation as therapy for HIV and Mycobacterium tuberculosis co-infection under conditions of iron overload. Curr Pharm Design 2006; 12(16): 1943-1947. [2] Pumfery A, de la Fuente C, Berro R, Nekhai S, Kashanchi F, Chao S-H. Potential Use of Pharmacological Cyclin-Dependent Kinase Inhibitors as Anti-HIV Therapeutics. Curr Pharm Design 2006; 12(16): 1949-1961. [3] Pöhlmann S, Reeves JD. Cellular entry of HIV: Evaluation of therapeutic targets. Curr Pharm Design 2006; 12(16): 1963-1973. [4] Varier RA, Kundu TK. Chromatin modifications (Acetylation/ Deacetylation/ Methylation) as new targets for HIV therapy. Curr Pharm Design 2006; 12(16): 1975-1993. [5] Christopher ME, Wong JP. Recent developments in delivery of nucleic acid-based antiviral agents. Curr Pharm Design 2006; 12(16): 1995-2006......

Iron chelators, as treatment for conditions of iron overload, have implications for AIDS and tuberculosis (TB) since excess iron in the system assists HIV and Mycobacterium tuberculosis (M.tb) multiplication. Excess iron, especially due to dietary habits, is almost as common in sub-Saharan Africa as infections by the two organisms. That HIV and M.tb influence each other's replication during co-infection is well established, but in vitro evaluations of concurrent infection of the two under conditions of iron overload and determining whether chelators reverse the effect, are limited. This review provides brief commentary on the possibility of iron chelators presently in clinical use influencing simultaneous HIV-M.tb infections during iron loading and the feasibility of evaluating this in vitro.

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and RNA polymerase II transcription. Several pharmacological CDK inhibitors (PCIs) are currently in clinical trials as potential cancer therapeutics since CDK hyperactivation is detected in the majority of neoplasias. Within the last few years, the anti-viral effects of PCIs have also been observed against various viruses, including human immunodeficiency virus (HIV), herpes simplex virus, and murine leukemia virus. Through the inhibition of CDK2 and 9, the cellular co-factors for HIV-1 Tat transactivation, HIV-1 replication is blocked by two specific PCIs, CYC202 and flavopiridol, respectively. In this article, we will review the inhibitory mechanisms of flavopiridol and CYC202 and discuss their possible usage in AIDS treatment.

In the absence of a vaccine which could stop the HIV/AIDS pandemic, the development of therapeutic options is of utmost interest. The combined use of inhibitors of reverse transcriptase and protease as highly active antiretroviral therapy (HAART) provided the first effective treatment of HIV/AIDS and significantly decreased the number of AIDS related deaths in industrialized countries. However, the emergence of resistant viruses and the toxic side effects of HAART highlights that novel therapies are urgently required. The inhibition of HIV-1 entry is a promising option. Entry of HIV-1 into target cells involves interactions of the viral envelope protein (Env) with CD4 and a coreceptor, usually CCR5 or CXCR4. Env binding to receptor triggers several conformational rearrangements in Env, which involve the creation and/or exposure of structural intermediates pivotal to fusion of the viral and cellular membranes. Both, cellular receptors and structures in Env associated with membrane fusion are targets for therapeutic intervention. Here, we will discuss how HIV-1 enters cells and introduce strategies how this process can be inhibited.

Human immunodeficiency virus (HIV) is one of the most deadly threats to the human race. Though the developed countries have been able to control the epidemic by utilizing the discovery of very expensive diagnostics, the situation is dangerously alarming in developing and underdeveloped countries. However, development of highly active antiretroviral drugs has improved the survival and quality of life, but prolonged treatment results in viral load rebound to pretherapy levels. Recent advances in our understanding of eukaryotic and genome- integrated viral gene expression showed that regulation of chromatin function is closely linked to the multiplication of HIV. Therefore, a new therapeutic approach has been initiated targeting the chromatin-modifying enzymes mainly histone acetyltransferases and deacetylases which may lead to a better and economical anti- HIV combinatorial therapeutics. In this review, we have discussed the mechanisms of HIV gene expression in the chromatin context and its potentiality to be exploited as new therapeutic target.

Rapid advances in viral genomics, gene function and regulation, as well as in rational drug design, have led to the development of gene-based drugs that can induce protective antiviral immunity, interfere with viral replication, suppress viral gene expression or cleave viral mRNAs. Several such drug candidates have been developed in recent years against various viruses including HIV. Although gene-based agents show promise as anti-viral agents their therapeutic efficacy may be restricted by limited delivery to intracellular sites of viral replication and in vivo nuclease degradation. Enhancement of the efficacy of gene-based drugs by encapsulation within liposomes or insertion within viral vectors has been evaluated. This review will highlight recent developments in delivery systems used to target nucleic acid-based drugs into sites of viral replication, therefore avoiding potential drug toxicity in non-viral infected organs. Liposomeencapsulation and insertion of nucleic acid-based drugs within viral vectors can significantly enhance antiviral efficacies. Viral vector-mediated therapy usually results in greater expression of the gene-based drug than with liposome delivery, however significant safety concerns have been raised in regards to viral vector therapies. Research is ongoing to increase drug delivery to the desired target cells while eliminating adverse side effects.

The mammalian immune system eliminates pathogens by generating a specific antibody response. Polyclonality is a key feature of this immune response: the immune system produces antibodies which bind to different structures on a given pathogen thereby increasing the likelihood of its elimination. The vast majority of current recombinant antibody drugs rely on monospecific monoclonal antibodies. Inherently, such antibodies do not represent the benefits of polyclonality utilized by a natural immune system and this has impeded the identification of efficacious antibody drugs against infectious agents, including viruses. The development of novel technologies has allowed the identification and manufacturing of antigen-specific recombinant polyclonal human antibodies, so-called symphobodies. This review describes the rationale for designing drugs based on symphobodies against pathogenic viruses, including HIV, vaccinia and smallpox virus, and respiratory syncytial virus.

Therapeutic HIV vaccines represent promising strategy as an adjunct or alternative to current antiretroviral treatment options for HIV. Unlike prophylactic AIDS vaccines designed to prevent HIV infection, therapeutic vaccines are given to already infected individuals to help fight the disease by modulating their immune response. The first immunotherapeutic trial in AIDS patients was conducted in 1983. Since then several dozen conventional therapeutic vaccine trials have been carried out. Unfortunately, the results have consistently shown that while HIV-specific immune responses were evident as a result of vaccination, the clinical improvement has been seldom observed. The instances of the apparent clinical benefit were invariably associated with unconventional vaccines that acted in accord with the principles of alloimmunization and/or autologous vaccination. All such vaccines were derived from the blood of HIV carriers or a cell culture and thus they inherently contained allo- or self-antigens unrelated to HIV. This intriguing observation raises the issue whether this clinically successful approach has been unduly neglected. The current strategy biased toward vaccines, which have shown little evidence of clinical efficacy, needs to be diversified and supplemented with research on alternative vaccine approaches geared toward immune tolerance induction.

Although combinations of drugs that target the HIV reverse transcriptase and protease enzymes have clearly revolutionized the treatment of HIV/AIDS, problems with these agents, such as viral escape mutants, persistence of viral reservoirs, poor patient compliance due to complicated regimens, and toxic side effects, have emphasized the need for development of new drugs with novel mechanisms of action, as well as an HIV vaccine. Recently two new classes of drugs have been identified that interfere with the membrane fusion reaction required for HIV entry of target cells. Two such agents, T-20 (enfuvirtide) and T-1249, which have been approved by the Food and Drug Administration (FDA), block the action of the fusogenic envelope glycoprotein gp41. Others target the HIV coreceptors CCR5 and CXCR4, and are now in clinical trials. Also under development are novel agents that target the HIV integrase and HIV regulatory gene products as well as immunomodulators such as IL-12 and IL-2. This article will focus on these and other novel approaches to HIV therapeutics.

Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity, mortality, hospital admissions, and decline in physical function and exercise capacity in congestive heart failure (CHF) patients. These therapeutic effects are attributed primarily to beneficial cardiovascular actions of these drugs. However, it has been suggested that ACE inhibitorinduced positive effects may also be mediated by direct action on the skeletal muscle. In particular, two recently published observational studies documented that among hypertensive subjects free of CHF, treatment with ACE inhibitors was associated with better performance and muscular outcomes and genetic studies also support the hypothesis that the ACE system may be involved in physical performance and skeletal muscle function. Effects on the skeletal muscle are probably mediated by mechanical, metabolic, anti-inflammatory, nutritional, neurological and angiogenetic actions of these drugs. These studies may have major public health implications for older adults, as consequence of the fact that, in this population, gradual loss of muscle mass and muscle strength can play a key role in the onset and progression of disability. Therefore, if findings of observational studies will be later confirmed in randomized controlled trials, ACE inhibitors could represent an effective intervention to prevent physical decline in the elderly, leading to greater autonomy in this growing population.