BSP :: Anti-Infective Agents in Medicinal Chemistry Home Page

Contents

Editorial Pp.1-1
Tarek S. Mansour and Phaik-Eng Sum
[Editorial In PDF]

Current Status of Anti-HIV Agents Pp.3-28
V.K. Tandon and R.B. Chhor
[Abstract] [Full text article]

Treatment Strategy Issues for Chronic HIV-1 Infection in Adults: The Dilemma of Life-long Antiretroviral Treatment Pp.29-36
Jean-Paul Viard
[Abstract] [Full text article]

Targeting Nucleotide Dimers Containing Antiviral Nucleosides Pp.37-54
L. Rossi, S. Serafini, P. Franchetti, L. Cappellacci, A. Fraternale, A. Casabianca, G. Brandi,F. Pierige, C-F Perno, E. Balestra, U. Benatti, E. Millo, M. Grifantini and M. Magnani
[Abstract] [Full text article]

Antiviral Compounds Derived from Naturally Occurring Proteins Pp.55-66
Antonio Pellegrini and Monika Engels
[Abstract] [Full text article]

Prophylactic and Therapeutic Approaches Against Respiratory Syncytial Virus Pp.67-73
Silvina Coviello and Fernando P. Polack
[Abstract] [Full text article]

Should We Develop an Inhaled Anti-pneumococcal Vaccine for Adults? Pp.75-89
Stephen B. Gordon and Neil French
[Abstract] [Full text article]

Abstracts

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Editorial
Tarek S. Mansour and Phaik-Eng Sum
[Editorial In PDF]

The last decade has witnessed substantial growth in all areas of anti-infectives. While new chemical entities have recently been described in the literature against certain molecular targets, many challenges remain in the future. Inhibition of entry into HIV-1 by fusion/entry inhibitors serves as an example of an evolving area in antiviral therapy. Conformational changes in Env protein as a result of fusion between viral CD4 and host cell chemokine coreceptors represent an attractive strategy for HIV-1 inhibition that stimulated investigating clinical development of many compounds. Yet, the variable Env target will likely pose many challenges in using such inhibitors. Another example relates to the recent advances in the treatment of hepatitis C infection by combination therapy with interferon-a and ribavirin and the emergence of new antiviral agents in clinical trials provides cause for optimism either for improved interferon combinations or single agents in the management of hepatitis C infections.

An interesting trend for the discovery of new antibacterial agents is based on genomics and bioinformatics approaches. A relatively large number of novel essential targets have been proposed. Genomic approaches, coupled with biochemical studies, are also useful in understanding modes of action of antibacterial agents. Related technologies, such as high-throughput screening, have clearly played a key role in identifying leads for optimization. The search for new chemical entities based on novel bacterial targets remains an important goal due to the increasing rate of bacterial resistance to all classes of antibiotics in clinical use.

Invasive antifungal infections, particularly in immunocompromised patients, are limiting our arsenal of antifungal agents. New agents are clearly needed to compliment current strategies and advances in this area. It seems that improved diagnosis of fungal infections is needed and many advances have been noted here. In addition, advances in new formulations of approved agents and delivery systems may be valuable in benefiting from pharmacokinetics data.

Twenty-two excellent review articles were published in four issues of Volume 3. These reviews span all three major areas of anti-infectives research: antivirals, antibacterials and antifungals. The emphasis of the journal is on the medicinal chemistry aspect of anti-infectives, and promising agents. We encourage submission of reviews on comparative structure activity relationship analyses, technologies in inhibiting certain targets, mechanistic studies, synthesis and biological properties of new agents and validation of new targets of potential therapeutic intervention, as well as pharmacokinetic/pharmacodynamic relationships.

An important milestone achieved this year is that the journal is now indexed in Chemical Abstracts, BIOSIS, EMBASE/Excerpta Medica and Cambridge Scientific Abstracts. This will provide wider exposure for the scientific contributions of the review articles published in CMC-AIA. Clearly, the Editorial Advisory Board and the publishers are pleased with this milestone. Moreover, the journal is under consideration by ISI for impact factor calculation.

In August, a newsletter was sent to the Advisory Editorial Board providing them with useful updates. This newsletter is now sent monthly and is targeted to establish a feedback loop between the publisher, co-editors and the Board. Because of the valuable target of enhancing the communication and feedback between all involved, the current Advisory Board will be modified by providing a chance for new members to participate and change some members due to the evolving nature of review articles. We encourage greater participation by our Advisory Board to continue advancing the journal’s objectives. We take this opportunity to thank our past Advisory Editorial Board members for their efforts and welcome the new members.

The list to credit for all these achievements is long. We thank the referees for their time and effort in reviewing the articles. The hard working and enthusiastic team of the journal, particularly Ms. Afshan Siddiq, is greatly acknowledged. We also thank Ms. Michele Markey of Wyeth Research for her support.

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Current Status of Anti-HIV Agents
V.K. Tandon and R.B. Chhor
[Full text article]

A large number of chemical enteties, immunogens and topical medications, either synthetic or naturally occuring, against HIV have been brought into focus to combat AIDS epidemic. The three major classes of anti-HIV medications, leading to the development of synthetic drugs worldwide, belong to NRTs, NNRTIs and protease inhibitors. These have been discussed in detail with regard to HIV infected patients. A large number of natural products isolated from various plant species, flora and fauna have been described in detail. Some of these compounds have the potential for development as future drugs for cure of AIDS and could be helpful in replacement of combination therapy presently prevalent for treatment of HIV patients. Proteomics and Genomics are vital cores of biotechnology for prime consideration in lead generation aginst HIV. The recent aspects of development of combination therapy as well as the development of vaccines for treatment of AIDS, which are of current interest to clinicians, biologists and medicinal chemists also being discussed.

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Treatment Strategy Issues for Chronic HIV-1 Infection in Adults: The Dilemma of Life-long Antiretroviral Treatment
Jean-Paul Viard
[Full text article]

Highly active antiretroviral therapy regimens (usually three-drug combinations) have shown undisputable efficacy in the reduction of the morbidity and mortality of HIV-infected patients. However, these regimens are only virustatic, which means that, in order to suppress viral replication, treatments should be maintained for life, without any additional benefit over time once immune restauration has been obtained. Besides, there is a debate on when to start therapy because profound immunodepression may not be totally reversible, recognizing that earlier treatment means longer drug exposure. On the other hand, the long-term toxicity of these drugs has generated new problems such as the appearance of the lipodystrophy syndrome and the increase of cardiovascular morbidity observed in patients treated for several years, particularly with HIV protease inhibitor-containing regimens. Therefore, new drugs are needed, not only for patients experimenting virological failure but also for successfully treated patients, in order to reduce toxicity, and these new drugs must now be screened for metabolic disturbances and adipocyte toxicity as well as for antiretroviral activity. Alternatively, new strategies, such as specific or non-specific immune-based therapy, reinforcing drug efficacy or allowing treatment interruptions, must be developed.

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Targeting Nucleotide Dimers Containing Antiviral Nucleosides
L. Rossi, S. Serafini, P. Franchetti, L. Cappellacci, A. Fraternale, A. Casabianca, G. Brandi,F. Pierige, C-F Perno, E. Balestra, U. Benatti, E. Millo, M. Grifantini and M. Magnani
[Full text article]

Among the antiviral agents developed for the treatment of human viral infections, nucleoside analogs represent the largest group. However, much remains to do to improve their pharmacokinetic properties, to increase their efficacy, to reduce the selection of drug-resistent strains and to reduce their toxic side effects. Towards this end many nucleotide dimers have been synthesized in the last years in several laboratories. Such compounds have several advantages compared to the administration of nucleoside analogs as single drugs: 1) can act as prodrugs for a slow delivery of monomers in circulation; 2) can be encapsulated into autologous erythrocytes to perform as bioreactors converting a non diffusible dimer into a diffusible nucleoside analog to be released in circulation; 3) can be targeted to macrophages by proper drug targeting systems; 4) can overcome the limiting phosphorylating activities of several infectable cell types; 5) can have the advantage of a combination therapy with the administration of a single compound. In this review, dimers developed in our laboratory will be reported. In particular, the heterodinucleotide AZTpPMPA and the homodinucleotide Bis-PMEA are shown to be able to act as prodrugs when administered to mice releasing the single monomer in circulation. The homodinucleotide AZTp₂AZT and the dimer AZTp₂EMB once encapsulated in human erythrocytes are converted by erythrocyte enzymes into diffusible nucleosides and slowly released from the carrier cells. The dimers AZTp₂AZT, AZTp₂ACV, ACVpPMPA, AZTpPMPA and Bis-PMEA were targeted to macrophages where a very effective protection against virus replications was obtained. Thus, nucleotide dimers could be used as effective prodrugs for drug delivery in the treatment of viral infections improving the pharmacokinetic of single moieties and can be efficiently targeted to selected cell types with intracellular release of a phosphorylated (active) nucleoside.

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Antiviral Compounds Derived from Naturally Occurring Proteins
Antonio Pellegrini and Monika Engels
[Full text article]

Food proteins have been considered till recently as substances that provide the organism with essential amino acids necessary for the maintenance of life. In more recent times it has been shown in a convincing manner that they are able to deliver the organism with several bioactive peptides including those possessing antiviral activity. A food protein, lactoferrin, has been shown to inhibit the human immunodeficiency virus, herpes simplex virus, human cytomegalovirus, poliovirus and rotavirus in vitro highlighting the importance of naturally occurring food proteins as possible antiviral agents. Of particular interest is that some food proteins, like a-lactalbumin or β-lactoglobulin, without antiviral activity can be modified, through easy chemical reactions, to acquire antiviral properties. One of the most successful modifications performed on the proteins, consists of chemically modifying the hydrophobic site and the positive charge of lysine and arginine residues of proteins by 3-hydroxyphthalic anhydride. The results reported until now suggest that multiple mechanisms are involved in the inhibition of the viral infection by the proteins investigated. Digestion of some proteins by proteolytic enzymes present in the gastrointestinal tract yields several peptide fragments possessing antiviral properties. Food proteins and their derivatives have the advantage, compared to synthetic pharmacologic compounds, to be non-toxic and surely well accepted by the consumers and thus have great potential for therapeutic application in the future.

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Prophylactic and Therapeutic Approaches Against Respiratory Syncytial Virus
Silvina Coviello and Fernando P. Polack
[Full text article]

RSV is the main viral respiratory cause of hospitalization in infants and young children in the United States and in the world. This manuscript discusses the different established and experimental approaches to prevention and treatment of respiratory syncytial virus disease. Therapeutic and preventive strategies are examined considering the mechanisms of viral pathogenesis and protection.

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Should We Develop an Inhaled Anti-pneumococcal Vaccine for Adults?
Stephen B. Gordon and Neil French
[Full text article]

Streptococcus pneumoniae is the most important bacterial cause of pneumonia and meningitis among adults. It is also a common cause of bacteraemia among HIV infected adults with rates of disease approaching 100 times normal community incidence figures. Rates of antibiotic resistance are rising among pneumococcal isolates globally and the currently available 23-valent pneumococcal polysaccharide vaccine is ineffective in HIV infected adult populations. The newer conjugate vaccine has been highly effective in children in the developed world. It may also offer some promise in adult risk populations, but it is expensive and has limited serotype coverage. This article reviews the epidemiology of pneumococcal disease, the current state of pneumococcal vaccines, the pathogenesis of pneumococcal disease, the potential advantages of an inhaled vaccine in adults and some of the chemical obstacles to producing such a vaccine.