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 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 90 <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.

Novel 2-(Diphenylmethylidene) Malonic Acid Derivatives as Anti-HIV Agents: Molecular Modeling, Synthesis and Biological Evaluation

“…Docking results revealed that all compounds accommodated well in the binding sites with binding energies ranging from -5.7 to -10.1 kcal/mol ( Figure 6 ). Most compounds demonstrated binding energies similar to the reference molecules, and in some compounds ( 8 , 9 , 11 , 16 ), the binding energies to the RT enzyme were even better than that of the reference molecule. Compounds 4 and 16 indicated high binding affinities for HIV PR and RT binding sites with ∆G values of -8.4 and -10.1 kcal/mol, respectively.…”

“…Then, a methanolic solution of compound 15 (1.5 g, 6.5 mmol) was added, and the mixture was stirred for 48 hours at room temperature. The resulting precipitate was collected by filtration under vacuum, washed with water and dried to afford compound 16…”

“…Hence, more studies are needed to improve the suitability of these compounds. Compounds 10,11,and 16, containing an amidoxime function, with EC 50 values of 25, 60.1, and 22 µM were identified as reasonable candidates for further investigations to find new anti-HIV hit compounds, especially considering the similar toxicity of AZT to these compounds. In contrast, compound 15 showed higher toxicity at 10 µM that could be due to the presence of two cyano groups in the molecule (56).…”

“…On the other hand, the use of designed multiple ligands (DMLs), which are single scaffolds with multiple biological targets, is a growing endeavor in medicinal chemistry ( 14 , 15 ). Reverse transcriptase (RT), integrase (IN), and protease (PR) are three essential HIV enzymes that are targeted by the commonly-used anti-HIV drugs, including RT, PR, and IN inhibitors ( 1 , 16 ). A new group of DMLs can be developed by modeling the chemical structures of these three classes and combining their main pharmacophores ( 17 ).…”

Impact of novel microbial secondary metabolites on the pharma industry

“…The mode of action of this compound is different from all current clinical anti-HIV drugs. It shuts down de novo virus production by inhibiting HIV gene expression and effectively inhibits a spectrum of clinical isolates, including all HIV genotypes (HIV-type 1 and HIV-type 2) (Herrmann et al 2020 ).…”