Novel four-disulfide insulin analog with high aggregation stability and potency. Issue 1 (12th November 2019)

• Record Type: Journal Article
• Authors: Xiong, Xiaochun; Blakely, Alan; Karra, Prasoona; VandenBerg, Michael A.; Ghabash, Gabrielle; Whitby, Frank; Zhang, Yi Wolf; Webber, Matthew J.; Holland, William L.; Hill, Christopher P.; Chou, Danny Hung-Chieh
• Is Part Of: Chemical science. Volume 11:Issue 1(2020)
• Page Start: 195
• Page End: 200
• Publication Date: 2019-11-12
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c9sc04555d
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : A novel four-disulfide insulin analog was designed with retained bioactivity and increased fibrillation stability. Abstract : Although insulin was first purified and used therapeutically almost a century ago, there is still a need to improve therapeutic efficacy and patient convenience. A key challenge is the requirement for refrigeration to avoid inactivation of insulin by aggregation/fibrillation. Here, in an effort to mitigate this problem, we introduced a 4 th disulfide bond between a C-terminal extended insulin A chain and residues near the C-terminus of the B chain. Insulin activity was retained by an analog with an additional disulfide bond between residues A22 and B22, while other linkages tested resulted in much reduced potency. Furthermore, the A22-B22 analog maintains the native insulin tertiary structure as demonstrated by X-ray crystal structure determination. We further demonstrate that this four-disulfide analog has similar in vivo potency in mice compared to native insulin and demonstrates higher aggregation stability. In conclusion, we have discovered a novel four-disulfide insulin analog with high aggregation stability and potency.