Protein α‐Turns Recreated in Structurally Stable Small Molecules

Hoang, Huy N.; Driver, Russell W.; Beyer, Renée L.; Malde, Alpeshkumar K.; Le, Giang T.; Abbenante, Giovanni; Mark, Alan E.; Fairlie, David P.

doi:10.1002/anie.201105119

Cited by 20 publications

(25 citation statements)

References 30 publications

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“…Noteworthy is also the observation of strong NOEs between the amide proton of Ala 1 and the H γ1,2 of Glu 4, as expected from the intended cyclization (Figure c). However, as mentioned above, 3 J αHN coupling measurements are more in agreement with an alpha turn as previously reported (Hoang et al, , ) (Figure d), with a characteristic large value (~10 Hz) for the residue in position 2 of the N‐lock. Not surprisingly, no NOEs were observed with the corresponding linear tetrapeptide (not shown).…”

Section: Resultssupporting

confidence: 91%

“…Rather, the helix can be stabilized by hydrogen bonding between such amides and the side‐chain hydrogen bond acceptor atoms of capping residues (Asn, Ser, Thr, Asp, or Glu) at positions 1 and 4 (Figure a), and such arrangement, termed capping box, is often found in native protein structures (Harper & Rose, ; Jimenez, Munoz, Rico, & Serrano, ; Presta & Rose, ). Based on this simple observation, it was reported that a straightforward way to stabilize a linear peptide into a helix could be via a direct lactam bond between the N‐terminus amine and the side chain of a glutamic acid placed in position 4 (Figure b) (Hoang et al, , ). While simple molecular mechanics would predict that such arrangement is compatible to an ideal alpha‐helical peptide geometry (Figure b), more detailed studies using molecular dynamics and experimental CD amd NMR data in solution suggested that the peptide is slightly distorted and assumes an alpha turn conformation (Hoang et al, , ).…”

Section: Resultsmentioning

confidence: 99%

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N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

et al. 2020

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Recently, it was reported that tetrapeptides cyclized via lactam bond between the amino terminus and a glutamic residue in position 4 (termed here N‐lock) can nucleate helix formation in longer peptides. We applied such strategy to derive N‐locked covalent BH3 peptides that were designed to selectively target the anti‐apoptotic protein Bfl‐1. The resulting agents were soluble in aqueous buffer and displayed a remarkable (low nanomolar) affinity for Bfl‐1 and cellular activity. The crystal structure of the complex between such N‐locked covalent peptide and Bfl‐1 provided insights on the geometry of the N‐locking strategy and of the covalent bond between the agent and Bfl‐1.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

et al. 2020

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“…Structures were calculated in XPLOR-NIH [9b] using a dynamic simulated annealing protocol in a geometric force field and energy-minimized using the CHARMm force field. Pro6 and Ile1(Thz) form an a-turn [10] at the other end of 3. 0.2 ) or dihedral angle (!…”

Section: Angewandte Zuschriftenmentioning

confidence: 99%

Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable

et al. 2014

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The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation.

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“…Ghadiri and co-workers, for instance, 20,21 have used copper-mediated azide-alkyne cycloadditions to give the 13-membered rings E which were conformationally rigid. 22 In other illustrative work, Fairlie et al substituted β-amino acids into cyclic tetrapeptides and found some 13-membered ring systems, including F 23 and G 24 , that could be prepared efficiently, and were conformationally rigid. However, that same work showed similar, but conformationally heterogeneous , 13-membered ring systems.…”

Section: Introductionmentioning

confidence: 99%

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

Xin

Burgess

2016

Org. Biomol. Chem.

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Each amino acid in a peptide contributes three atom units to main-chains, hence natural cyclic peptides can be 9, 12, 15, …. ie 3n membered-rings, where n is the number of amino acids. Cyclic peptides that are 9 or 12-membered ring compounds tend to be hard to prepare because of strain, while their one amino acid homologs (15-membered cyclic pentapeptides) are not conformationally homogeneous unless constrained by strategically placed proline or D-amino acid residues. We hypothesized that replacing one genetically encoded amino acid in a cyclic tetrapeptide with a rigid β-amino acid would render peptidomimetic designs that rest at a useful crossroads between synthetic accessibility and conformational rigidity. Thus this research explored non-proline containing 13-membered ring peptides 1 featuring one anthranilic acid (Anth) residue. Twelve cyclic peptides of this type were prepared, and in doing so the viability of both solution- and solid-phase methods was demonstrated. The library produced contained a complete set of four diastereoisomers of the sequence 1aaf (ie cyclo-AlaAlaPheAnth). Without exception, these four diastereoisomers each adopted one predominant conformation in solution; basically these conformations feature amide N-H vectors puckering above and below the equatorial plane, and approximately oriented their N-H atoms towards the polar axis. Moreover, the shapes of these conformers varied in a logical and predictable way (NOE, temperature coefficient, D/H exchange, circular dichroism). Comparisons were made of the side-chain orientations presented by compounds 1aaa in solution with ideal secondary structures and protein-protein interaction interfaces. Various 1aaa stereoisomers in solution present side-chains in similar orientations to regular and inverse γ-turns, and to the most common β-turns (types I and II). Consistent with this, compounds 1aaa have a tendency to mimic various turns and bends at protein-protein interfaces. Finally, proteolytic- and hydrolytic stabilities of the compounds at different pHs indicate they are robust relative to related linear peptides, and rates of permeability through an artificial membrane indicate their structures are conducive to cell permeability.

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Protein α‐Turns Recreated in Structurally Stable Small Molecules

Cited by 20 publications

References 30 publications

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

N‐locking stabilization of covalent helical peptides: Application to Bfl‐1 antagonists

Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable

Anthranilic acid-containing cyclic tetrapeptides: at the crossroads of conformational rigidity and synthetic accessibility

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