Design and Folding of [GluA4(OβThrB30)]Insulin (“Ester Insulin”): A Minimal Proinsulin Surrogate that Can Be Chemically Converted into Human Insulin

Sohma, Youhei; Hua, Qing; Whittaker, Jonathan; Weiss, Michael A.; Kent, Stephen B. H.

doi:10.1002/anie.201001151

Cited by 70 publications

(52 citation statements)

References 26 publications

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“…36–39 Further complicating matters, to our knowledge, the total synthesis of glycosylated insulin has not been reported. 12 That said, total chemical synthesis of glycoproteins has made significant strides in the past decade, and over 20 glycoproteins have been made chemically.…”

Section: Resultsmentioning

confidence: 99%

Chemically Precise Glycoengineering Improves Human Insulin

et al. 2017

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Diabetes is a leading cause of death worldwide and results in over 3 million annual deaths. While insulin manages the disease well, many patients fail to comply with injection schedules, and despite significant investment, a more convenient oral formulation of insulin is still unavailable. Studies suggest that glycosylation may stabilize peptides for oral delivery, but the demanding production of homogeneously glycosylated peptides has hampered transition into the clinic. We report here the first total synthesis of homogeneously glycosylated insulin. After characterizing a series of insulin glycoforms with systematically varied O-glycosylation sites and structures, we demonstrate that O-mannosylation of insulin B-chain Thr27 reduces the peptide’s susceptibility to proteases and self-association, both critical properties for oral dosing, while maintaining full activity. This work illustrates the promise of glycosylation as a general mechanism for regulating peptide activity and expanding its therapeutic use.

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Section: Resultsmentioning

confidence: 99%

Chemically Precise Glycoengineering Improves Human Insulin

et al. 2017

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“…[71] As aconsequence of the high degree of foldability of this ester-insulin and its conversion into fully active human Lys,Pro-insulin, Kent and co-workers have developed an efficient modular synthesis of this ester-insulin based on the convergent native chemical ligation of three synthetic fragments of similar size (Scheme 11). [71] As aconsequence of the high degree of foldability of this ester-insulin and its conversion into fully active human Lys,Pro-insulin, Kent and co-workers have developed an efficient modular synthesis of this ester-insulin based on the convergent native chemical ligation of three synthetic fragments of similar size (Scheme 11).…”

Section: Assembly Of Single-component Insulin Precursors By Oxime Ligmentioning

confidence: 99%

Insulin—From its Discovery to the Industrial Synthesis of Modern Insulin Analogues

Moröder

Musiol

2017

Angew Chem Int Ed

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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.

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“…[3] Both synthetic and recombinant peptides can be used in native chemical ligation. [5] Although native chemical ligation is a transformative method, its applicability can sometimes be limited in two respects: 1) peptide thioesters remain challenging to synthesize with Fmoc chemistry; [6] 2) convergent synthesis of larger proteins without using protecting groups requires an "orthogonal" amide-forming ligation chemistry, that is, one that is compatible with the use of native chemical ligation. [5] Although native chemical ligation is a transformative method, its applicability can sometimes be limited in two respects: 1) peptide thioesters remain challenging to synthesize with Fmoc chemistry; [6] 2) convergent synthesis of larger proteins without using protecting groups requires an "orthogonal" amide-forming ligation chemistry, that is, one that is compatible with the use of native chemical ligation.…”

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confidence: 99%