Human Il-2Rα Subunit Binding Modulation of Il-2 Through a Decline in Electrostatic Interactions: A Computational and Experimental Approach Publisher Pubmed



Parikhani AB^{1, 2} ; Bagherzadeh K^{3, 4} ; Dehghan R^{1, 2} ; Biglari A⁵ ; Shokrgozar MA⁶ ; Rad FR⁷ ; Zeinali S⁸ ; Talebkhan Y⁹ ; Ajdary S⁷ ; Cohan RA¹⁰ ; Behdani M¹
Source: PLoS ONE Published:2022

Abstract

Although high-dose IL-2 has clear antitumor effects, severe side effects like severe toxicity and activation of Tregs by binding of IL-2 to high-affinity IL-2R, hypotension, and vascular leak syndrome limit its applications as a therapeutic antitumor agent. Here in this study, a rational computational approach was employed to develop and design novel triple-mutant IL-2 variants with the aim of improving IL-2-based immunotherapy. The affinity of the mutants towards IL-2Rα was further computed with the aid of molecular dynamic simulations and umbrella sampling techniques and the obtained results were compared to those of wild-type IL-2. In vitro experiments by flow cytometry showed that the anti-CD25 mAb was able to bind to PBMC cells even after mutant 2 preincubation, however, the binding strength of the mutant to α-subunit was less than of wtIL-2. Additionally, reduction of IL-2Rα subunit affinity did not significantly disturb IL-2/IL2Rβγc subunits interactions. © 2022 Beig Parikhani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.