Structural design of IL10 to obtain more effective drugs with lower affinity against IL10Rb and decoupled pro- and anti-inflammatory functions

IL10 is well known for its anti-inflammatory effects. However, it could also trigger pro-inflammatory functions. Hyper-inflammation during severe COVID-19 cases is associated with a drastic elevation of IL10 production. High IL10 levels could be an indicator of poor outcomes. Given these circumstances, the design of IL10 variants with decoupled pro-inflammatory effects would restore the therapeutic applicability of IL10. In this regard, we have exploited in silico tools for cell-type-specific modulation of IL10 function on immune cells. Low-affinity IL10 variants were designed against the IL10Rb to perturb the IL10/IL10Rb interaction in cells with low expression of IL10Rb. The cells with high expression of the IL10Rb would not be affected by affinity alteration. Saturation mutation, molecular docking, and binding affinity calculations were performed using various in silico tools. The obtained results indicated that the Lys34Pro, Asp28Arg, and Asp28Lys were the most efficient mutations to lower the IL10 binding affinity while preserving the key interface amino acids of the original IL10/IL10Rb complex. Among the Asp28Arg variant failed to decrease the binding affinity, whereas the Lys34Pro and Asp28Lys variants decreased the binding affinity against IL10Rb compared to the wild-type IL10. The Lys34Pro variant also shared a more similar binding orientation and interface amino acids in complex with the IL10Rb. Designing low-affinity IL10 variants via bioinformatics approaches would bring about huge therapeutic advantages. Various immunological complications could be targeted by low-affinity IL10 variants with decoupled pro- and anti-inflammatory effects. • IL10 variants with decoupled pro-inflammatory effects would restore the therapeutic applicability of IL10. • Low affinity IL10 variants against the IL10Rb are designed to perturb the IL10/IL10Rb interaction. • The cells with high expression of the IL10Rb would not be affected by decreased affinity of IL10. • The cells with low expression of the IL10Rb would be affected by designed decreased affinity of IL10. • Designed low affinity IL10 molecules would trigger stronger anti-inflammatory effects. • Low affinity IL10 variants would bring about huge therapeutic advantages in fight against cytokine storm.