Current Medicinal Chemistry - Anti-Infective Agents - Volume 2, Issue 3, 2003

Higher plants have evolved into efficient biochemical defense mechanisms, which comprised of a wide variety of secondary compounds including alkaloids, flavonoids, terpenoids and saponins. Induction of secondary plant metabolism in cells, tissues and organ cultures do provide a potential alternative to the use of the whole plant or total synthesis of the active components. In vitro manipulation of plant secondary products offers biotechnological techniques to exploit cultured plant cell metabolism. In spite of the fact that very few plant cell processes are operating commercially, the most successful commercial pharmaceuticals produced from undifferentiated cell cultures are antibiotic compounds. The naphthoquinone shikonin from Lithospermum erythrorhizon is an anti-inflammatory, the isoquinoline alkaloid berberine from Coptis japonica is an intestinal antiseptic and the oral antimicrobial benzo-phenanthridine alkaloid sanguinarine from Papaver bracteatum are well known examples. Moreover, intensive research studies is currently devoted to produce the anti-leukaemic alkaloids vinblastine and vincristine from Catharanthus roseus, the antimalaria artemisinin from Artemisia annua and the anti-ovarian cancer taxol from Taxus brevifolis. The scope of this review is to analyze the successful in vitro production examples of antimicrobial agents, to give examples of novel chemical structures produced by plant cell cultures and not reported from the corresponding parent plants and to highlight the potential of biotransformation, elicitation and transformation techniques for the production of antiinfective agents from plant cell, tissue and organ cultures.

The opportunistic human pathogen Pseudomonas aeruginosa, which causes fatal lung infections in cystic fibrosis patients, regulates the expression of virulence factors by N-acyl-Lhomoserine lactone (AHL) mediated gene expression. AHL mediated gene expression, also known as quorum sensing, involves the production of and response to a small diffusible metabolite. This gene expression mechanism allows populations of P. aeruginosa to coordinate expression of virulence factors to maximise the success of infection. AHL mediated gene expression offers a new target for the control of bacterial infection that is not dependent on the use of compounds with antibiotic activity. This review summarises investigations that have demonstrated the efficacy of marine natural products in inhibiting AHL mediated gene expression and controlling P. aeruginosa infection.

The search for potent antiviral agents is urgent in view of the dramatic situation of the global HIV / AIDS epidemic, a possible spread of avian influenza and of other viral diseases. Effective antiviral therapeutics are not available, and the presently approved therapy for HIV (HAART) has been recognized to be toxic, unable to eradicate the causative virus and to induce severe drug resistance. In this situation, more attention should be paid to the search for antiviral agents present in natural products. Marine or fresh water algae are one of the richest sources of bioactive compounds, and have only marginally been investigated. The present review summarizes the antiviral and immunomodulatory properties of algae or extracts thereof which have been investigated in numerous in vitro and animal,studies: i) for approximately four decades it has been known that sulfated polysaccharides, extracted from algae, exhibit a potent broad-spectrum antiviral activity in vitro against HIV-1, HIV-2 and a large variety of other enveloped viruses. These compounds interfere with the attachment of the virus to its target cells,thereby inhibiting virus-cell fusion i.e.the entry of the virus into its target cells , ii) cyanovirin N is a 11 kDa polypeptide ,isolated from blue-green algae, that interferes with multiple steps in the membrane fusion process associated with the entry of HIV-1 into CD4+ cells.The antiviral polypeptide also inhibits HSV-6 and measles virus in vitro, iii) sulfoglycolipids (sulfoquinovosyldiacylglycerols) were discovered in cyanobacteria . Presently several antiviral sulfoglycolipids have been isolated and their mechanism of action was shown to be an inhibition of the reverse transcriptase (RT) of HIV-1 and HIV-2, iv) The immunomodulatory properties of algae and algal compounds were known for over a decade: carrageenans and other natural or synthetic sulfated polysaccharides are potent T and B cell mitogens in vitro. In recent studies, whole cyanobacteria preparations (Spirulina), given as food, were shown in animal tests to increase phagocytic activity,increase antibody production,increase accumulation of NK cells into tissue,and to mobilize T and B cells into blood. Algae thus appear to have the potential of a novel therapy system: a combination of antiviral agents, targetting two different steps in the viral replication cycle ,plus immunostimulating agents,which may support synergistically the antiviral effects. Tests of this system in humans are urgently needed, and may provide the base for safe and efficient future antiviral therapeuticals.

Several nucleoside or nucleoside phosphonate analogues that were discovered as selective inhibitors of the replication of herpesviruses and the human immunodeficiency virus (HIV) have been identified as effective inhibitors of the replication of the hepatitis B virus (HBV). These include (i) dideoxynucleoside analogues that lack hydroxyl groups at both the 2' and 3' of the ribose moeity [e.g. 2',3'-dideoxy-3'-fluorothymidine, FLT], (ii) dioxolane nucleoside analogues in which the 3' carbon of the ribose ring has been replaced by oxygen [e.g. 1-β-D-2,6-diaminopurine dioxolane (DAPD)], (iii) the carbocyclic nucleoside analogues in which the oxygen in the furanose ring is replaced by a carbon [ e.g. cyclopentyl guanine (entecavir)], (iv) 2'-fluorinated pyrimidine nucleoside analogues [e.g. 2'-deoxy-2'-fluoro-1-β-D-arabinofuranosyl-5-iodouracil (FIAC)], (v) iso dideoxynucleoside analogues in which the furanose oxygen is moved to the C3 position (vi) acyclic nucleoside analogues with a truncated open sugar ring structure [e.g. penciclovir], (vii) acyclic nucleoside phosphonate analogues with a phosphonylmethylether group in place of the phosphate moiety [e.g. adefovir], (viii) L-nucleoside analogues which are enantiomers of the ‘natural’ β-D-nucleoside analogues [e.g. lamivudine] and the (ix) cyclobutyl nucleoside analogues which contain a four-membered glycosyl ring [e.g. lobucavir]. Recently also some selective non-nucleoside inhibitors of HBV replication have been identified, these include (i) phenylpropenamide derivatives (ii) iminosugars, a class of cyclic sugar derivatives in which the ring oxygen is replaced by a nitrogen atom and (iii) a class of heteroaryl pyrimidines. Currently only lamivudine and the oral prodrug form of adefovir, i.e. adefovir dipivoxil have been approved for the treatment of chronic HBV infections.

Adverse events secondary to mitochondrial toxicity is an emerging problem related to treatment of HIV infection with nucleoside reverse transcriptase inhibitors (NRTI). The prevailing hypothesis of mitochondrial toxicity associated with these agents is mitochondrial DNA (mtDNA) depletion as a result of inhibition of the mtDNA polymerase, DNA polymerase γ (DNA Pol γ). However, the inhibition of DNA Pol γ may not be the sole mechanism of mtDNA depletion. Recently, mutations in deoxyribonucleoside kinase (DRNK) genes have been discovered in children with mtDNA depletion syndromes. DRNK are involved in the maintenance of the mitochondrial deoxynucleotide (mtdNTP) pools and in the metabolism of NRTI, and may play a pivotal role in NRTI related mitochondrial toxicity. Studies which focus on the role DRNK in NRTI induced mtDNA depletion and mitochondrial toxicity are needed. It is possible that identifying a mutation or polymorphism in one of the DRNK enzymes could predict differential toxicities between individual and combination NRTI, and could identify which patients are at risk for NRTI-associated mitochondrial toxicity. In addition, elucidating this mechanism could lead to the development of adjunctive drugs or substrates that could ameliorate these toxicities. This review focuses on the following topics: 1) NRTI induced adverse events, 2) Mechanism of NRTI induced mitochondrial toxicity, 3) Summary of clinical and laboratory evidence, 4) Evidence for mechanisms other than DNA Pol g associated mitochondrial toxicity 5) The role of DRNK in mtDNA depletion and relation to activated NRTI induced toxicity, and 6) Considerations for future studies to elucidate the mechanism and to prevent NRTI toxicity.