Stereoselective synthesis and structural elucidation of dicarba peptides

Gleeson, Ellen C.; Wang, Zhen J.; Robinson, Samuel D.; Chhabra, Sandeep; MacRaild, Christopher A.; Jackson, W. Roy; Norton, Raymond S.; Robinson, Andrea J.

doi:10.1039/c5cc10540d

Cited by 15 publications

(7 citation statements)

References 50 publications

(4 reference statements)

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“…As with other dicarba peptide sequences, only minor differences in carbon chemical shifts were observed between the two isomers, with the major difference occurring at the C β atoms of the dicarba bridge (Fig. S2 ) 25 . Consistent with the previously reported model for stereochemical assignment, the upfield C β shifts for the cis isomer presented at δ30.9 and δ32.8 and those for the trans isomer appeared at δ36.4 and δ36.9.…”

Section: Resultssupporting

confidence: 54%

“…Additionally, an independent, stereoselective synthesis of cis -[A6–11]-dicarba insulin A chain ( Z- 3 ) (Fig. SI l ) was achieved using a preformed, orthogonally protected Z- configured diaminosuberic acid residue ( cis- S1 ) 25 and SPPS (Fig. S3 ) and found to be identical to material obtained via RCM (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…The C β chemical shifts of peptides comprising Δ 4 -diaminosuberic acid (Δ 4 Sub) residues show appreciable differences between the cis-(Z ) and trans-(E) configurations 25 . These features were used to identify the stereochemistry of the insulin A-chain A6-A11 dicarba bridge without the need for structural calculations.…”

Section: Resultsmentioning

confidence: 99%

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Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

Lierop

Ong

Belgi

et al. 2017

Sci Rep

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The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro. Further biophysical, crystallographic and molecular-dynamics analyses reveal that the A6-A11 bond configuration directly affects the conformational flexibility of insulin A-chain N-terminal helix, dictating insulin’s ability to engage its receptor. We reveal that in native insulin, contraction of the Cα-Cα distance of the flexible A6-A11 cystine allows the A-chain N-terminal helix to unwind to a conformation that allows receptor engagement. This motion is also permitted in the cis isomer, with its shorter Cα-Cα distance, but prevented in the extended trans analogue. These findings thus illuminate for the first time the allosteric role of the A6-A11 bond in mediating the transition of the hormone to an active conformation, significantly advancing our understanding of insulin action and opening up new avenues for the design of improved therapeutic analogues.

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Section: Resultssupporting

confidence: 54%

Section: Resultsmentioning

confidence: 95%

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Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

Lierop

Ong

Belgi

et al. 2017

Sci Rep

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“…Saturated dicarba bridge mimetics were initially installed in peptide sequences using orthogonally-protected 2,7-diaminosuberic acid residues [127][128][129]. The use of olefin metathesis and hydrogenation to achieve the same end has more recently been facilitated through the development of functional-group-tolerant Grubbs ruthenium(II)-alkylidene catalysts.…”

Section: Dicarba Bridgesmentioning

confidence: 99%

α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

Kennedy

Belgi

Husselbee

et al. 2020

Toxins

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Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets—nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABAB) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.

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“…To explore the significance of conformational restriction, we introduced different rigidifying elements at the lysine side chain having the same number of core atoms, but less conformational freedom. The three selected analogues are: (i) K E , an unsaturated lysine having an (E)-configured double bond between the gand d-positions, 17 (ii) K Z , an unsaturated lysine having a (Z)-configured double bond between the gand d-positions, 18,19 and (iii) K yne , an unsaturated lysine having a triple bond between the gand d-positions (Fig. 1c).…”

mentioning

confidence: 99%

Methylation of geometrically constrained lysine analogues by histone lysine methyltransferases

Temimi¹,

White²,

Mulders³

et al. 2020

Chem. Commun.

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Stereoselective synthesis and structural elucidation of dicarba peptides

Cited by 15 publications

References 50 publications

Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

Methylation of geometrically constrained lysine analogues by histone lysine methyltransferases

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