Reverse transcriptase TOPICAL

Foscarnet is an inorganic pyrophosphate analogue which causes selective inhibition of viral DNA polymerase and reverse transcriptase. Topical foscarnet cream has appeared to be a safe and effective treatment for aciclovir-unresponsive mucocutaneous herpes simplex virus infection in AIDS patients. 

Efavirenz is a non-nucleoside reverse transcriptase inhibitor with excellent inhibitory activity against HTV-l. Its most frequent adverse effects involve the central nervous system and the skin (1). At the start of therapy, dizziness, insomnia, or fatigue is observed in most patients, and headache and even psychotic reactions have also been observed. A maculopapular rash is seen in about 10%. These adverse effects usually vanish within the first 2-4 weeks of therapy (2). About 1-2% of individuals stop taking efavirenz because of neurological or dermatological adverse events. Administration of efavirenz at bedtime reduces the incidence of severe adverse effects, and the rash can be managed by short-term antihistamines or topical corticosteroids (1). Nausea and vomiting are less often observed than in patients treated with zidovudine, lamivudine, or indinavir. 

Three commercial assays for viral load determination are currently available Quantiplex (Chiron), NASBA (Organon-Teknika), and Amplicor (Roche). Only the latter would fall into the topic of this chapter (see Note 1), because it is based on the RNA- or reverse transcriptase-polymerase chain reaction (RT-PCR) technique. 

The mechanism of actions involves tubulin binding, reverse transcriptase inhibition, integrase inhibition and topoisomerase inhibition. Podophyllo-toxins bind to tubulin and are able to disrupt the cellular cytoskeleton and interfere with some vital virus processes. There is no relationship between the inhibition of reverse transcriptase (RT) and chemical structure in the case of lignans, because all the chemical antiviral structures are able to bind to the enzyme. As to the rest of the mechanism, there is not much information available. The effects of rabdosiin may be due to its topoisomerase inhibitory effects. Charlton concluded that the antiviral activity of lignans is not strong and that except for podophyllotoxin, which is used topically to treat various warts caused by HPV, none of them are of interest for commercial application. 

Few topics are closer to the heart of the medicinal chemist than heterocycles. Heterocyclic compoxmds form the centerpiece of the most important classes of antibiotics, such as the beta-lactams (penicillin), macrolide lactones (erythromycin), and more recently the quinolones, but the reach of heterocyclic structures in bioactive molecules goes far beyond these examples. One needs to only consider the antimalarials quinine and artemisinin, the anti-HIV reverse-transcriptase inhibitors (e.g., AZT and 3TC), and the important anticancer agents— vincristine and pemetrexed— to begin to see the role that heterocycles play in our world today. 

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