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Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin.

ABSTRACT: Overcoming the global health threat of HIV infection requires continuous pipelines of novel drug candidates. We identified the ?-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.

SUBMITTER: Herrmann A

PROVIDER: S-EPMC6987146 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin.

Herrmann Alexander A Roesner Manfred M Werner Thomas T Hauck Stefanie M SM Koch Alisha A Bauer Amelie A Schneider Martha M Brack-Werner Ruth R

Scientific reports 20200128 1

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 (IC<sub>90</sub><45 nM), photostability and improved cell safety. Co ...[more]

PMID: 31992748

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Project description:BackgroundThe illicit use of synthetic opioids such as fentanyl has led to a serious public health crisis in the US. People with opioid use disorder are more likely to contract infections such as HIV and viral hepatitis and experience more severe disease. While several drugs of abuse are known to enhance viral replication and suppress immunologic responses, the effects of synthetic opioids on HIV pathogenesis have not been investigated thoroughly. Thus, we examined the impact of fentanyl on HIV replication and chemokine receptor expression in the U937 cell line and monocyte-derived macrophages (MDMs).MethodsU937 cells were exposed to varying concentrations of fentanyl. Expression levels of the CXCR4 and CCR5 chemokine receptors were measured in cell lysates. HIV p24 antigen was quantified in culture supernatants by ELISA, and HIV proviral DNA was quantified in cells using SYBR real-time PCR targeting the pol gene. RNAseq was performed to characterize cellular gene regulation in the presence of fentanyl.ResultsFentanyl induced HIV p24 expression and proviral DNA levels in U937 cells and in primary MDMs. The opioid antagonist naltrexone blocked the effect of fentanyl and reversed the expression of HIV protein and proviral DNA. Fentanyl led to a non-significant decrease in CXCR4 and CCR5 protein levels in U937 cells. RNA sequencing identified several differentially expressed genes in cells infected with HIV and exposed to fentanyl compared to infected cells with no drug exposure. Several microRNAs were also differentially expressed upon fentanyl exposure but not at a statistically significant level.ConclusionThese data demonstrate that the synthetic opioid fentanyl can promote HIV replication in macrophages. As higher HIV levels lead to accelerated disease progression and a higher risk of transmission to others, further research is needed to better understand opioid-virus interactions and to develop new and/or optimized treatment strategies for people living with HIV and opioid use.

Dataset Information

Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin.

Publications

Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin.

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