Controlling Curvature in a Family of Oligoamide α‐Helix Mimetics

Saraogi, Ishu; Incarvito, Christopher D.; Hamilton, Andrew D.

doi:10.1002/anie.200803778

Cited by 51 publications

(37 citation statements)

References 51 publications

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“…2E). We and others have previously noted that this intramolecular hydrogen bond leads to increased curvature in the mimetic backbone, 18,[22][23][24] in this case, potentially improving its binding interaction by providing a better shape match with the surface of IAPP helices. The role of the alkyl ether substituent is less clear: while both isopropyl compounds 16 and 19 gave the greatest increases in cell viability, benzamide 16 gave only weak inhibition of fibrillization in vitro.…”

Section: A-helix Mimeticsmentioning

confidence: 74%

“…All compounds tested displayed a measurable inhibitory effect. The mimics containing pyridylamides (19 and 20) caused a significantly longer delay before the onset of fibrillization than the oligobenzamides (16)(17)(18), suggesting that the structural preorganization caused by the formation of an intramolecular hydrogen bond in the pyridylamides is advantageous in terms of their inhibitory effect (Fig. 2B).…”

Section: A-helix Mimeticsmentioning

confidence: 98%

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Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Kulikov

Kumar

Magzoub

et al. 2015

Tetrahedron Letters

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a b s t r a c tThe abnormal deposition of proteins as insoluble plaques is associated with many diseases, including Alzheimer's, Parkinson's and type II diabetes. There is an unmet need for synthetic agents that are able to mediate particular steps in the pathway between soluble proteins in their native unfolded state and their insoluble b-sheet rich aggregates. We have previously reported classes of a-helix mimetic that agonize or antagonize islet amyloid polypeptide aggregation, depending on the presence of a lipid bilayer. Here we investigate a novel mixed benzamide and pyridylamide scaffold that gives improved activity and explores the role of side-chain polarity, backbone rigidity and curvature in inhibiting lipid-catalyzed fibrillization.Ó 2015 Published by Elsevier Ltd.The deposition of protein aggregates (amyloidosis) is a characteristic of the pathology of many disease classes including Alzheimer's, Parkinson's, prion diseases, and type II diabetes. 1-3 Typically, misfolding of the native protein leads to extended and highly stable b-sheet oligomers, which undergo further aggregation to ultimately form proteolysis-resistant fibrils. However, the precise oligomeric intermediates involved in amyloidosis, and the mechanism by which they aggregate remains an unsolved problem. In the case of type II diabetes, the protein that undergoes misfolding is the intrinsically disordered 37-residue hormonal peptide islet amyloid polypeptide (IAPP). We have previously described the role played by membrane-bound aggregates of a-helical intermediate conformers en-route to forming b-oligomers from the intrinsically disordered native structure of IAPP (Fig. 1A). 4 This provides an opportunity to retard amyloidosis by stabilizing or disrupting these a-helical intermediates, thus preventing progression of the disease pathology.The oligobenzamide and oligopyridylamide classes of a-helix mimic provide a scaffold from which the phenol ether substituents accurately reproduce the spatial and angular projection of the sidechains at residues i, i + 3/4 and i + 7 of a natural a-helix (Fig. 1B). [5][6][7][8][9][10][11][12] The transient a-helical domain of IAPP is known to contain multiple cationic side-chains, hence we have utilized benzamide and pyridylamide homo-oligomers with complementary polyanionic carboxylate side-chains for the inhibition of IAPP aggregation. [13][14][15][16] However, the use of exclusively anionic side-chains is an oversimplification: the relevant cationic residues of IAPP (e.g., Arg11 and His18) occupy the (i) and (i + 7) positions, with the intercalated (i + 3/4) residues either lipophilic (Phe15) or neutral and polar (Asn14). 15 Recently we described the incorporation of a lipophilic side-chain in the central (i + 3/4) position, leading to increased potency in the oligopyridylamide series. 17 Here we outline the synthesis of a series of oligobenzamides and mixed benzamidepyridylamide trimeric helix mimetics possessing amphiphilic side-chain substituents (Fig. 1B). We seek to understand the role played by ...

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Section: A-helix Mimeticsmentioning

confidence: 74%

Section: A-helix Mimeticsmentioning

confidence: 98%

Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Kulikov

Kumar

Magzoub

et al. 2015

Tetrahedron Letters

Self Cite

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“…Since our initial report in 2007 (ref. 26), the ability of the oligo-benzamide scaffolds to mimic helical structures and disrupt PPIs have been further established [33][34][35][36] . We also demonstrated that the oligo-benzamidebased peptidomimetics can easily be synthesized by using simple and uncomplicated reactions with high yields 30 .…”

Section: D2 Inhibits Ar Expression In Human Tumours Cultured Ex Vivomentioning

confidence: 99%

Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer

et al. 2013

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The growth of advanced prostate cancer depends on androgen receptor signalling, however treatment options are limited. Here we report the disruption of specific protein-protein interactions involving LXXLL motifs in androgen receptor-coregulator proteins such as PELP1 using a novel, small molecule peptidomimetic (D2). D2 is stable, non-toxic and efficiently taken up by prostate cancer cells. Importantly, D2 blocks androgen-induced nuclear uptake and genomic activity of the androgen receptor. Furthermore, D2 abrogates androgen-induced proliferation of prostate cancer cells in vitro with an IC 50 of 40 nM, and inhibits tumour growth in a mouse xenograft model. D2 also disrupts androgen receptor-coregulator interactions in ex vivo cultures of primary human prostate tumours. These findings provide evidence that targeting androgen receptor-coregulator interactions using peptidomimetics may be a viable therapeutic approach for patients with advanced prostate cancer.

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“…One such scaffold is aromatic oligoamides 2, which have structural rigidity due to intramolecular hydrogen bonding (Figure 1c). Because they are easily prepared by a modular synthesis and have improved water solubility [32,33], aromatic oligoamides are an attractive scaffold and widely utilized as a-helix mimetics [32,[34][35][36][37][38][39][40][41]. For example, recently, Wilson and co-workers have utilized trisbenzamides as an a-helix mimetic scaffold to develop inhibitors of the interaction between hypoxia inducible factor-1a (HIF-1a) and p300 [39 ].…”

Section: Small Focused Libraries Of A-helix Mimeticsmentioning

confidence: 99%

Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein–protein interactions

Moon

Lim

2015

Current Opinion in Chemical Biology

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Controlling Curvature in a Family of Oligoamide α‐Helix Mimetics

Cited by 51 publications

References 51 publications

Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer

Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein–protein interactions

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