Current Medicinal Chemistry - Anti-Infective Agents - Volume 4, Issue 1, 2005

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.

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.

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.

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 α-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.

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.

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.