Parniak M, Borkow G, Sluis-Cremer N, Klinski E, Alakhov V; International Conference on AIDS.

Int Conf AIDS. 2000 Jul 9-14; 13: abstract no. WePeA4057.

M. Parniak, McGill University AIDS Centre, Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada, Tel.: +1-514-340-8260, Fax: +1-514-340-7502, E-mail: mparniak@ldi.jgh.mcgill.ca

Background and Objectives: N-(4-tert-butylbenzoyl)-2-hydroxy-1-naphthaldehyde hydrazone (BBNH) inhibits both the DNA polymerase and the ribonuclease H activities of HIV-1 reverse transcriptase (RT) (Borkow et al (1997) Biochemistry 36:3179). BBNH inhibits HIV replication, but has unfavorable toxicity due to chelation of cellular iron. The preformed Fe(III)BBNH chelate is significantly more potent against HIV-1 RT in vitro compared to BBNH, but has little aqueous solubility and shows no antiviral activity in vitro due to inability to enter cells. Formulation of Fe(III)BBNH with a non-ionic copolymer carrier yielded SP1093V, which gives excellent aqueous solubility to the inhibitor and allowed us to characterize the in vitro antiviral properties of SP1093V. Results and Conclusions: SP1093 V was a potent inhibitor of acute HIV-1 and HIV-2 infection of MT2 cells (EC50 = 1 uM), with low cytotoxicity (CC50>100 uM). SP1093V inhibited both laboratory and clinical HIV-1 isolates, and showed equivalent antiviral potency against wt, NRTI-resistant and NNRTI-resistant HIV-1 strains. SP1093V pretreatment of uninfected cells protected these cells against subsequent HIV infection in the absence of exogenous drug. SP1093V treatment of HIV-1 chronically-infected H9 cells did not affect virus assembly or production, but the nascent virus were significantly attenuated in infectivity (EC50 = 0.3 uM for this effect). SP1093 V thus appears to inhibit HIV replication at both pre-integrational and post-integrational stages, a property unique among current anti-HIV drugs. SP1093 V could have promise as a salvage treatment for patients failing on current combination therapies.

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Vaccines
• Acquired Immunodeficiency Syndrome
• Anti-HIV Agents
• Antiviral Agents
• DNA-Directed DNA Polymerase
• HIV Infections
• HIV Seropositivity
• HIV-1
• HIV-2
• Humans
• In Vitro
• antagonists & inhibitors
• reverse transcriptase, Human immunodeficiency virus 1

Other ID:

• GWAIDS0002724

UI: 102240218

From Meeting Abstracts