Related Experiment Videos
Structure-activity relationships in platelet-activating factor (PAF). 10. From PAF antagonism to inhibition of HIV-1
N Serradji1, O Bensaid, M Martin
1Unité de Recherche Pharmacochimie Moléculaire et Systèmes Membranaires, Laboratoire de Pharmacochimie Moléculaire, Université Paris, France.
Abstract:
Excessive levels of PAF and cells of macrophage lineage appear to play an important role in neuronal cell injury, inflammatory syndrome, and HIV replication in CNS resulting in AIDS dementia complex (ADC). The beneficial effects of PAF receptor antagonists are evident and give rise to expected therapeutic strategies for neurotrauma. Piperazine derivatives bearing a "cache-oreilles" (ear-muff) electronic distribution are able to inhibit in vitro PAF effects and, thus, could be used in pathologies where this mediator is involved. Therefore, their potential anti-HIV activity was investigated, and we find that (i) these PAF antagonists are effectively active in HIV-infected monocyte-derived macrophages (MDM) but there is no correlation between both anti-HIV and anti-PAF activities; (ii) the presence of a carbamate function (compounds 1a-d) is favorable to the antiviral activity; (iii) the lipophilicity of the substituent on the piperazinic cycle seems to be less important for the anti-PAF activity than for the antiviral one. Our leading compound, PMS 601 (compound 1a), presents a dual activity with IC(50) of 8 and 11 microM for anti-PAF and anti-HIV activity, respectively, without cytotoxic events at 1000 microM in MDM. Although its mode of action is not clearly defined, these data suggest that PMS 601, which displays no effect on acellular reverse transcriptase or protease tests, deserves further investigation in the treatment of HIV-1-associated dementia.
Insights
New piperazine derivatives show dual activity against Platelet-Activating Factor (PAF) and HIV replication in brain cells. Compound PMS 601 is a promising candidate for treating HIV-associated dementia (ADC) without cytotoxicity.
Area of Science:
- Neuroscience
- Virology
- Pharmacology
Background:
- Platelet-Activating Factor (PAF) and macrophage lineage cells contribute to neuronal injury, inflammation, and HIV replication in the central nervous system (CNS), leading to AIDS dementia complex (ADC).
- PAF receptor antagonists offer potential therapeutic strategies for neurotrauma and related conditions.
Purpose of the Study:
- To investigate the potential anti-HIV activity of piperazine derivatives designed to inhibit PAF effects.
- To evaluate the correlation between anti-PAF and anti-HIV activities and identify key structural features for antiviral efficacy.
Main Methods:
- Synthesis and in vitro testing of piperazine derivatives, including those with carbamate functions.
- Assessment of anti-PAF and anti-HIV activities in HIV-infected monocyte-derived macrophages (MDM).
- Evaluation of cytotoxicity and effects on viral enzymes (reverse transcriptase, protease).
Main Results:
- Piperazine derivatives demonstrated anti-HIV activity in MDM, independent of their anti-PAF effects.
- The presence of a carbamate group enhanced antiviral activity.
- Compound PMS 601 exhibited dual activity (anti-PAF and anti-HIV) with IC50 values of 8 and 11 microM, respectively, and showed no cytotoxicity at 1000 microM.
- PMS 601 did not inhibit acellular reverse transcriptase or protease activity.
Conclusions:
- Piperazine derivatives, particularly PMS 601, possess significant anti-HIV and anti-PAF activities relevant to CNS pathologies.
- PMS 601 is a promising dual-acting compound for further investigation in the treatment of HIV-1-associated dementia.
- Structural modifications, like carbamate presence and lipophilicity, influence antiviral efficacy.