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 acytokine 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 circulatoryhalf-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 flexibleC-termini of hIFNγ, but also includes the upstream nuclear localization sequence (NLS) of themolecule, 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 © 2020 Author(s)
In silico indications for human interferon gamma inhibition by heparin