Abstract
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.
Highlights
IntroductionSeveral classes of antiretroviral drugs have been developed, which are effective at inhibiting different steps of the HIV-1 life cycle
The initial screen was performed using a HIV-1 based vector that was pseudotyped with the vesicular stomatitis virus G-protein (VSV-G) and expressed the green fluorescent protein (GFP) (16)
Systematic analysis of the HIV-1 life cycle showed that the small compounds inhibited an early step of the HIV-1 life cycle coincident with the establishment of an actively transcribing virus
Summary
Several classes of antiretroviral drugs have been developed, which are effective at inhibiting different steps of the HIV-1 life cycle. The potential value of this approach for antiviral drug development is highlighted by three genome-wide, high throughput screens based on small interfering RNA (siRNA) technology, which identified several hundred host cell factors important for HIV replication (9–11). Such studies are clearly important, it is difficult to predict which factors among the hundreds identified will be susceptible to modulation by small molecules and whether they represent a valid target for antiviral drug development
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
