In silico indications for human interferon gamma inhibition by heparin

Under acute inflammatory conditions, including COVID-19, elevated blood levels of certain cytokines lead to a life-threatening condition – severe cytokine release syndrome (CRS) also known as a cytokine storm, which can progress to a multiple organ failure and – in the most severe cases – to death. The inhibition and elimination of one of the major circulating over-expressed cytokines, hIFNγ, is a prerequisite for gaining control over the cytokine storm. As a possible means for achieving this goal we put forward heparin, in particular its low-molecular-weight derivatives (LMWH), widely used in the clinical practice as anticoagulants and known to limit hIFNγ circulatory half-life. Here we report the first results of a computational study of the interaction of hIFNγ and LMWH oligosaccharides based on 500ns long molecular dynamics simulations. The interaction is very strong and binding occurs on a few tens of ns timescale. In addition, the formed complexes are extremely stable. It is noteworthy that the interaction site is not just limited to the flexible C-termini of hIFNγ, but also includes the upstream nuclear localization sequence (NLS) of the molecule, that is – the domains, which are associated with the accomplishing of its biological function, ensuring the formation of the cytokine–receptor complex and the subsequent initiation of the signal transduction into the nucleus.