Moderator: Music Discussion, PM
- Aug 31, 2016
- Frostbite Falls, MN
Anti-HIV-1 activity of the iboga alkaloid congener 18-MC*
Silva, Cirne-Santos, Frugulhetti, Galvo-Castro, Saraiva, Kuehnem, Bou-Habib
Infection by the HIV-1 virus is a global health problem affecting more than 42 million people worldwide. HIV-1 persistently replicates in the lymphoid tissues, leading to a progressive deterioration of the immune system. An effective vaccine against HIV-1 infection has not been developed yet.
Two decades after the discovery of the first cases of AIDS, the clinical use of the abundant anti-retroviral repertoire has decreased the morbidity and mortality of HIV-1 infection. However, this treatment does not completely eradicate HIV-1 from the infected tissues, and its long-term use is restricted by metabolic disorders and toxicities, emergence of drug-resistant viruses and complex administration. Thus, the search for other anti-retroviral compounds is critical, and numerous new anti-HIV-1 agents that target different phases of viral replication cycle are under development or in clinical trials.
The Iboga-type indole alkaloid coronaridine is found in many species of the plant kingdom and has been studied for its potential anti-addictive properties. Because of the side effects such as tremor, cerebellar neurotoxicity and bradycardia associated with COR, chemical structure modifications were made to reduce its side effects, which was attained with a meth-oxylation at carbon-18, resulting in the Iboga analogue 18-methoxycoronaridine (18-MC).
Since many alkaloids have been described as capable of inhibiting HIV-1 infection in vitro, we investigated whether 18-MC is also endowed with anti-retroviral properties. We found that 18-MC inhibits HIV-1 replication in human peripheral blood mononuclear cells and in monocyte-derived macrophages, and that this activity is at least partially mediated by reducing the activity of the HIV-1 enzyme reverse transcriptase.
Results and discussion
In this paper, we report that the indole alkaloid congener 18-MC inhibits HIV-1 infection. The infection assays were performed with primary cells to avoid the genotypic and phenotypic changes that might occur during viral passages in tumor cell lines. We also used primary isolates, which are closer to the viral population present in HIV-1-infected patients.
In preliminary experiments, we found that naturally occurring COR decreased the infection in a dose dependent manner. Since 18-MC is an improved molecule of the natural compound coronaridine, presenting little to none of the adverse effects associated with the original molecule, we continued our anti-retroviral studies using the new alkaloid congener 18-MC.
Our present results warrant further investigation on the mechanisms by which 18-MC decreases HIV-1 replication in vitro. Considering that 18-MC demonstrates a vigorous leishmanicidal activity in vitro, its potential therapeutic properties may be uniquely useful for the treatment of HIV-1-infected individuals as well as patients co-infected with Leishmania and HIV-1.
*From the article here :