9th Conference on Retroviruses and Opportunistic Infections Seattle, Washington - February 24 -February 28, 2002

Conf Retroviruses Opportunistic Infect 2002 Feb 24-28;9:abstract no. 8
T. Yoshinaga¹, A. Sato¹, T. Fujishita¹, and T. Fujiwara^2
1Shionogi & Co. Ltd., Osaka, Japan and ²Shionogi USA, Inc., Florham Park, NJ

BACKGROUND: There is a pressing need for new antiretroviral classes with activity against resistant virus and with a novel mechanism of action. Integrase is an essential enzyme for HIV to integrate its proviral DNA into host cell chromosome. S-1360, a low molecular weight HIV-1 integrase inhibitor for oral use, was synthesized by Shionogi & Co. Ltd. and is under clinical development in the United States.

METHODS: Multi-well plate in vitro integrase enzyme inhibition assay, in vitro antiviral assay with HIV-1 III(B), drug resistant molecular clones and clinical isolates, and mouse-MT4 in vivo HIV replication model were used.

RESULTS: S-1360 showed potent in vitro integrase inhibition with an IC₅₀ of 20 nM. The EC₅₀, EC₉₀, and CC₅₀ values of S-1360 in MTT assay (MT-4 cells infected with IIIB) were 200 nM, 740 nM, and 12,000 nM, respectively. S-1360 resistant mutants were isolated in vitro and the amino acid substitutions responsible for drug resistance were in close proximity to the integrase active site. The role of the mutation in codon 66 and others conferring S-1360 resistance was confirmed by site-directed mutagenesis. S-1360 also demonstrated potent antiviral activity against a variety of clinical isolates. The mean EC₅₀, EC₉₀, and CC₅₀ values were 140 nM, 990 nM, and 110,000 nM. S-1360 was active against both X4 tropic and R5 tropic strains, and against known NRTI, NNRTI, and PI drug-resistant variants. S-1360 was synergistic in vitro in combination with various NRTIs, NNRTIs and PIs. S-1360 was also active in a mouse-MT4 in vivo assay and showed efficacy (ED₅₀, 7.1 mg/kg) similar to capravirine (ED₅₀, 10 mg/kg) and AZT (ED₅₀, 2 mg/kg).

CONCLUSION: S-1360 represents a new class of potent anti-HIV agents. These results coupled with acceptable pre-clinical safety and animal PK profiles support the currently ongoing clinical investigations.

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Copyright © 2002 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.