Biomimetic Synthesis of Lispro Insulin via a Chemically Synthesized “Mini-Proinsulin” Prepared by Oxime-Forming Ligation

Sohma, Youhei; Kent, Stephen B. H.

doi:10.1021/ja9052398

Cited by 66 publications

(49 citation statements)

References 25 publications

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“…Both aldehyde and aminooxy groups are favorable for the effective adjustment of intra-and inter-molecular interactions and further modification, such as chemoselective ligations as robust biomolecular hooks. [25][26][27][28][29][30][31] To confirm the existence of the highly branched structure of the HPOXs, 1 H NMR, 13 C NMR, 13 For the HPOXs, the DB was calculated from quantitative 13 C NMR analysis. As shown in Table 1, the DB of the HPOX samples range from 0.23 to 0.51, substantiating the highly branched architecture.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and self-assembly of nonamphiphilic hyperbranched polyoximes

et al. 2012

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Nonamphiphilic hyperbranched polyoximes (HPOXs) were successfully synthesized by the polycondensation of trialdehyde and bis-aminooxy monomers with different molar feeding ratios.Various characterization techniques, such as 1D and 2D nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), and multi-detector gel permeation chromatography (GPC) were used to identify the highly branched structure of the HPOXs. Despite there being no amphiphilic block segments, HPOXs with a torispherical structure could self-assemble into nanoparticles in a mixed solution of dimethyl sulfoxide and H 2 O. Besides, the modulation of the degree of branching (DB) and the terminal groups resulted in the appearance of spherical and bowl-shaped morphologies due to the change of the intra-and inter-molecular interactions. Accordingly, dynamic light scattering (DLS), transmission electron microscopy (TEM), atomic force microscopy (AFM), scanning electron microscopy (SEM), fluorescence spectroscopy (FL) together with ultraviolet and visible spectrometery (UV-vis) were employed to unravel the tentative mechanism of the formation of the HPOX selfassemblies. Moreover, dynamic oxime linkages and hydrogen bonds endowed the HPOX nanoparticles with pH and thermal dual responsiveness, which was confirmed by TEM measurements. HPOXs are developed to offer a novel pathway for the design of nonamphiphilic self-assemblies with dual responsiveness.

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Section: Resultsmentioning

confidence: 99%

Synthesis and self-assembly of nonamphiphilic hyperbranched polyoximes

et al. 2012

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“…4,5 In particular, where carbohydrates and amino acids are employed, the chemoselective nature of the oxime-forming reaction allows for the use of unprotected building blocks, even in the presence of a variety of other functional groups. To this end, many reports have been made of diverse aminooxy-containing molecules, including linkers, 6–9 polymers, 8,10 amino acids/peptides/proteins, 9,11 carbohydrates, 12,13 nanoparticles, 14 multivalent scaffolds, 15–18 etc. Molecules such as these have been utilized to create a variety of oxime-containing bioconjugates such as glycopeptides/glycoproteins, 19,20 drug conjugates, 21,22 and biopolymers.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of hydrophilic aminooxy linkers and multivalent cores for chemoselective aldehyde/ketone conjugation

McReynolds

Dimas

2014

Tetrahedron Letters

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A series of three linear and two trivalent aminooxy-containing hydrophilic linkers and cores were synthesized. The five molecules contain from one to three aminooxy groups, and all but one contain an ether for enhanced aqueous solubility. These unique and versatile molecules can be utilized in the chemoselective conjugation of aldehyde/ketone-containing molecules, including reducing sugars, under mild aqueous conditions, and give rise to oxime-containing conjugates useful in a wide variety of applications and studies. The value of these aminooxy-based molecules and the ease and speed of preparation of both monovalent and multivalent oxime-linked molecules is demonstrated in two examples using the disaccharide cellobiose; one with a linear linker, and the second with a trivalent core.

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“…They share the native linear order of proinsulin where the N-terminus of the A-chain is indirectly connected to the C-terminus of the B-chain. Conversion to the two-chain form initially employed enzymatic conversion and was restricted by the requirement for a unique proteolytic site [11][12][13][14][15] . The more recent reports employing chemically labile linkers represent a leap forward by eliminating the need for a proteolytic site, and the enzyme itself.…”

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confidence: 99%

Synthesis of disulfide-rich heterodimeric peptides through an auxiliary N, N-crosslink

et al. 2018

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Insulins, relaxins, and other insulin-like peptides present a longstanding synthetic challenge due to their unique cysteine-rich heterodimeric structure. While their three disulfide signature is conserved within the insulin superfamily, sequences of the constituent chains exhibit considerable diversity. As a result, methods which rely on sequence-specific strategies fail to provide universal access to these important molecules. Biomimetic methods utilizing native and chemical linkers to tether the A-chain N-terminus to the B-chain Cterminus, entail complicated installation, and require a unique proteolytic site, or a two-step chemical release. Here we present a strategy employing a linkage of the A-and B-chains Ntermini offering unrestricted access to these targets. The approach utilizes a symmetrical linker which is released in a single chemical step. The simplicity, efficiency, and scope of the method are demonstrated in the synthesis of insulin, relaxin, a 4-disulfide insulin analog, two penicillamine-substituted insulins, and a prandial insulin lispro.

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Biomimetic Synthesis of Lispro Insulin via a Chemically Synthesized “Mini-Proinsulin” Prepared by Oxime-Forming Ligation

Cited by 66 publications

References 25 publications

Synthesis and self-assembly of nonamphiphilic hyperbranched polyoximes

Synthesis and self-assembly of nonamphiphilic hyperbranched polyoximes

Synthesis of hydrophilic aminooxy linkers and multivalent cores for chemoselective aldehyde/ketone conjugation

Synthesis of disulfide-rich heterodimeric peptides through an auxiliary N, N-crosslink

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