ABSTRACT
The increasing frequency of filovirus outbreaks in African countries has led to a pressing need for the development of effective antifilovirus agents. In continuation of our previous research on the antifilovirus activity of monoterpenoid derivatives, we synthesized a series of (+)-fenchol and (-)-isopinocampheol derivatives by varying the type of heterocycle and linker length. Derivatives with an N-alkylpiperazine cycle proved to be the most potent antiviral compounds, with half-maximal inhibitory concentration (IC50) 1.4-20 µÐ against Lenti-EboV-GP infection and 11.3-47 µÐ against Lenti-MarV-GP infection. Mechanism-of-action experiments revealed that the compounds may exert their action by binding to surface glycoproteins (GPs). It was demonstrated that the binding of the synthesized compounds to the Marburg virus GP is less efficient as compared to the Ebola virus GP. Furthermore, it was shown that the compounds possess lysosomotropic properties. Thus, the antiviral activity may be due to dual effects. This study offers new antiviral agents that are worthy of further exploration.
Subject(s)
Antiviral Agents , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Humans , Virus Internalization/drug effects , Structure-Activity Relationship , Ebolavirus/drug effects , Molecular Structure , Dose-Response Relationship, Drug , Animals , Microbial Sensitivity Tests , Chlorocebus aethiops , Marburgvirus/drug effectsABSTRACT
A new series of heterocyclic derivatives with a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment was designed, synthesised and biologically evaluated. Synthesis of the target compounds was performed using the Cu(I) catalysed cycloaddition reaction. The key starting substances in the click reaction were an alkyne containing a 1,7,7-trimethylbicyclo[2.2.1]heptane fragment and a series of azides with saturated nitrogen-containing heterocycles. Some of the derivatives were found to exhibit strong antiviral activity against Marburg and Ebola pseudotype viruses. Lysosomal trapping assays revealed the derivatives to possess lysosomotropic properties. The molecular modelling study demonstrated the binding affinity between the compounds investigated and the possible active site to be mainly due to hydrophobic interactions. Thus, combining a natural hydrophobic structural fragment and a lysosome-targetable heterocycle may be an effective strategy for designing antiviral agents.
Subject(s)
Heptanes , Triazoles , Structure-Activity Relationship , Catalysis , Triazoles/pharmacology , Antiviral Agents/pharmacologyABSTRACT
Cohen syndrome is an autosomal recessive disorder caused by VPS13B (COH1) gene mutations. This syndrome is significantly underdiagnosed and is characterized by intellectual disability, microcephaly, autistic symptoms, hypotension, myopia, retinal dystrophy, neutropenia, and obesity. VPS13B regulates intracellular membrane transport and supports the Golgi apparatus structure, which is critical for neuron formation. We generated induced pluripotent stem cells from two patients with pronounced manifestations of Cohen syndrome and differentiated them into neural stem cells and neurons. Using transmission electron microscopy, we documented multiple new ultrastructural changes associated with Cohen syndrome in the neuronal cells. We discovered considerable disturbances in the structure of some organelles: Golgi apparatus fragmentation and swelling, endoplasmic reticulum structural reorganization, mitochondrial defects, and the accumulation of large autophagosomes with undigested contents. These abnormalities underline the ultrastructural similarity of Cohen syndrome to many neurodegenerative diseases. The cell models that we developed based on patient-specific induced pluripotent stem cells can serve to uncover not only neurodegenerative processes, but the causes of intellectual disability in general.