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Natural viral inhibitors

Nature inspired European researchers to design new viral inhibitors with potentially better bioactivity and higher selectivity. The project was extended to design and develop argyrin analogues that boast anti-cancer activity through direct targeting of the proteasome.
Natural viral inhibitors
The limited success of hepatitis C virus (HCV) and adverse side-effects encountered with HIV treatment strategies emphasise the need for non-toxic and more efficient alternatives.

The EU-funded ANTIVIRAL project followed a computer-based approach to identify natural compounds capable of protein binding. New, improved analogues were then synthesised by optimising docking parameters to treat HIV and HCV. As targets, scientists used the integrase enzyme for HIV, and the NS2-3, NS3-4A proteases and the NS5B RNA-dependent RNA polymerase for HCV.

Comprehensive computational and genetic analysis of HIV-1 and HCV inhibitors also provided a mechanistic explanation of the resistance against the approved HIV-1 integrase inhibitor. Based on these promising results, the activities of the ANTIVIRAL project were extended to include cancer.

Argyrins, a family of natural products, were identified as potential anti-cancer agents that directly inhibit proteasome activity, which is often aberrantly regulated in cancer. Currently, there are two clinically approved proteasome inhibitors for the treatment of cancer: bortezomib and carfilzomib.

In order to test the efficacy of argyrin A analogues, researchers prepared a 3D model of the human proteasome and used it to perform molecular docking experiments. This model enabled the design of argyrin A analogues with strict specificity for the different sub-units of the proteasome — a pre-requisite for proteasome inhibitors.

The high prevalence of cancer and virus infections renders the ANTIVIRAL approach a promising design methodology that uses natural compounds to develop novel inhibitors.

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