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Inhibition of HIV-1 Replication by Isoxazolidine and Isoxazole Sulfonamides

Loh, B; Vozzolo, L; Mok, BJ; Lee, CC; Fitzmaurice, RJ; Caddick, S; Fassati, A; (2010) Inhibition of HIV-1 Replication by Isoxazolidine and Isoxazole Sulfonamides. Chemical Biology and Drug Design , 75 (5) 461 - 474. 10.1111/j.1747-0285.2010.00956.x. Green open access


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Targeting host factors is a complementary strategy for the development of new antiviral drugs. We screened a library of isoxazolidine and isoxazole sulfonamides and found four compounds that inhibited HIV-1 infection in human CD4+ lymphocytic T cells with no toxicity at IC90 concentrations. Structure-activity relationship showed that benzyl sulfonamides and a halo-substituted aromatic ring on the heterocycle scaffold were critical for antiretroviral activity. The size and position of the incorporated halogen had a marked effect on the antiretroviral activity. The sulfonamide derivatives had no significant effect on HIV-1 entry, reverse transcription and integration but impaired a step necessary for activation of viral gene expression. This step was Tat-independent, strongly suggesting that the target is a cell factor. A virus partially resistant to the least potent compounds could be selected but could not be propagated in the long term, consistent with the possibility that HIV-1 may be less likely to develop resistance against drugs targeting some host factors. Here, we provide evidence that novel synthetic methods can be applied to develop small molecules with antiretroviral activity that target host factors important for HIV-1 replication.

Type: Article
Title: Inhibition of HIV-1 Replication by Isoxazolidine and Isoxazole Sulfonamides
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/j.1747-0285.2010.00956.x
Publisher version: http://dx.doi.org/10.1111/j.1747-0285.2010.00956.x
Language: English
Additional information: © 2010 John Wiley & Sons A/S. Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://www3.interscience.wiley.com/authorresources/onlineopen.html
Keywords: Gene expression, HIV-1, Novel Chemical Entity, Sulfonamides
URI: http://discovery.ucl.ac.uk/id/eprint/120627
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