Abstract
Overcoming the global health threat of HIV infection requires continuous pipelines of novel drug candidates. We identified the γ-pyrone polyketides Aureothin/Neoaureothin as potent hits by anti-HIV screening of an extensive natural compound collection. Total synthesis of a structurally diverse group of Aureothin-derivatives successfully identified a lead compound (#7) superior to Aureothin that combines strong anti-HIV activity (IC90<45 nM), photostability and improved cell safety. Compound #7 inhibited de novo virus production from integrated proviruses by blocking the accumulation of HIV RNAs that encode the structural components of virions and include viral genomic RNAs. Thus, the mode-of-action displayed by compound #7 is different from those of all current clinical drugs. Proteomic analysis indicated that compound #7 does not affect global protein expression in primary blood cells and may modulate cellular pathways linked to HIV infection. Compound #7 inhibited multiple HIV genotypes, including HIV-type 1 and 2 and synergistically inhibited HIV in combination with clinical reverse transcriptase and integrase inhibitors. We conclude that compound #7 represents a promising new class of HIV inhibitors that will facilitate the identification of new virus-host interactions exploitable for antiviral attack and holds promise for further drug development.
Highlights
With over 37 million individuals globally living with HIV, HIV infection represents a serious public health threat
Most clinical drugs inhibit steps of the replication cycle catalysed by HIV enzymes. combination antiretroviral therapy (cART) combines three active drugs, of which two are nucleotide or nucleoside reverse transcriptase (NRTI) inhibitors
Www.nature.com/scientificreports and the third is from a different class, i.e. a non-nucleoside reverse transcriptase inhibitor (NNRTI), protease or integrase inhibitor[1]
Summary
With over 37 million individuals globally living with HIV, HIV infection represents a serious public health threat. A major target of the global action plan for overcoming HIV/AIDS is the intensification of research for the development of new treatments and drugs. These are needed to improve individualization of antiretroviral therapy and to block HIV production by cell populations with persisting, integrated HIV proviruses. Compound #7 treatment inhibited expression of HIV structural components on protein and RNA levels. We conclude that this class of compounds has the potential to advance the development of novel anti-HIV therapeutic agents and to expand options for anti-HIV treatment
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 call
