Bioorganic Chemistry, Max-Planck Institute of Biochemistry, Am Klopferspitz 18, 82152, Martinsried, Germany.
Angew Chem Int Ed Engl. 2017 Aug 28;56(36):10656-10669. doi: 10.1002/anie.201702493. Epub 2017 Jul 24.
After the discovery of insulin as a drug for diabetes, the pharmaceutical companies were faced with the challenge to meet the demand for insulin with the highest possible degree of purity in the required quantities from animal sources. The observation of an immune reaction of patients to insulin from animal pancreatic extracts made the availability of human insulin of highest priority. Only the enzyme-catalyzed semisynthesis at the C-terminus of the insulin B-chain led to a commercial process, but it depended on porcine insulin and was aggravated by supply concerns. The advent of rDNA technology allowed the commercial preparation of human insulin by biosynthesis in virtually unlimited quantities. An increased chemical diversity was only envisaged through chemical synthesis, which was simplified by advances in solid-phase peptide synthesis and chemical ligation. Single-chain insulin precursors are now being synthesized that should enable fast screening of insulin analogues for improved biophysical, biological, and thus promising new therapeutic properties, as well as for the industrial manufacture of insulin analogues not accessible by biosynthesis.
胰岛素被发现可用于治疗糖尿病之后，制药公司面临着一项挑战，即需要从动物源中提取尽可能高纯度的胰岛素，以满足对胰岛素的需求。从动物胰腺提取物中观察到的胰岛素免疫反应使得获取高纯度的人胰岛素成为重中之重。只有通过胰岛素 B 链 C 末端的酶催化半合成，才能实现商业化生产，但该方法依赖于猪胰岛素，且供应问题也很严重。rDNA 技术的出现使得通过生物合成就可以大量制备商业用的人胰岛素。只有通过化学合成才能实现更大的化学多样性，而这一目标因固相肽合成和化学连接技术的进步而变得更加容易。目前正在合成单链胰岛素前体，这有望实现胰岛素类似物的快速筛选，从而获得改善的物理化学性质、生物学特性和更有前景的新治疗特性，同时也可以用于工业制造通过生物合成无法获得的胰岛素类似物。
