[Therapeutic potential of Ro 5-3335. New active benzodiazepine in vitro against HIV-1 viruses resistant or non-resistant to AZT].
Ro 5-3335 is a new benzodiazepine highly active in vitro (IC50 = 0.1-1.0 microM [corrected]) against HIV-1 viruses of AIDS resistant or non-resistant to zidovudine (AZT). It is also active against HIV-2. Ro 5-3335 is original by its mechanism of action, acting on the trans-activation factor of transcription (TAT) and non on the reverse transcriptase. Such as, it could prevent proviral DNA to express in both evolutive and silent AIDS resistant or non-resistant to AZT or to other anti-reverse transcriptase series. In addition, in antagonizing extracellular TAT's actions, Ro 5-3335 could alleviate the syndrome commonly associated with AIDS as Kaposi's syndrome. In rodent test, Ro 5-3335 has no diazepam-like central effects and presents in comparison to AZT a more favorable therapeutic index. In dog, the elimination half-life, peak concentration and availability are 2 h, 0.8 microM and 85% respectively, after a 1 mg.kg-1 oral dose of Ro 5-3335. Theoretically, Ro 5-3335 and now its analogue Ro 24-7429 seem to possess all virtues to antagonize evolutive and latent AIDS. Its arrival is timely to cope with the ever increasing resistance phenomena, lengthy development of AIDS vaccines, exponential contamination of populations worldwide and last but not least possibly to impede evolutions of the disease. Ability to manipulate TAT-mediated activation of HIV-1 genes paves the ways to study conceivable corrections of abnormal gene expressions of neurotransmitters, hormones, oncogenes and key enzymes.
Camsonne
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Service de Pharmacologie et des Explorations Fonctionnelles B, CHRU, Caen.
Bigot
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Fusibet
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Moulin
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D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001570:Benzodiazepinones / Q000494:pharmacology* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial; D015696:Gene Products, tat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D066298:In Vitro Techniques; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D015215:Zidovudine / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D001570:Benzodiazepinones; D015696:Gene Products, tat; D011758:Pyrroles; D054322:tat Gene Products, Human Immunodeficiency Virus; C072173:Ro 5-3335; D015215:Zidovudine
Potentiel thérapeutique du Ro 5-3335. Une nouvelle benzodiazépine active in vitro contre les virus HIV-1 résistants ou non à l'AZT.