Small molecule screening in context: Lipid‐catalyzed amyloid formation

Hebda, James A.; Magzoub, Mazin; Miranker, Andrew D.

doi:10.1002/pro.2518

Cited by 15 publications

(11 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lipid surface catalyzed amyloid formation serves as a downstream readout of events that may be associated with cell toxicity (Hebda, Magzoub, and Miranker, 2014). We therefore investigated the capacity of ADM-3 to affect cell toxicity and membrane permeation gains-of-function.…”

Section: Resultsmentioning

confidence: 99%

Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

Kumar

Schlamadinger

Brown

et al. 2015

Chemistry & Biology

100

View full text Add to dashboard Cite

SUMMARY Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin. IAPP proceeds through a series of conformational changes from random coil to β-sheet via transient α-helical intermediates. An unknown subset of these events are associated with seemingly disparate gains-of-function including catalysis of self-assembly, membrane penetration, loss of membrane integrity, mitochondrial localization and finally cytotoxicity, a central component of diabetic pathology. A series of small molecule, α-helical mimetics, oligopyridylamides, was previously shown to target the membrane bound α-helical oligomeric intermediates of IAPP. In this study, we develop an improved, microwave assisted synthesis of oligopyridylamides. A series of designed tripyridylamides demonstrate that lipid-catalyzed self-assembly of IAPP can be deliberately targeted. These molecules additionally affect IAPP induced leakage of synthetic liposomes and cellular toxicity in insulin secreting cells. The tripyridylamides inhibit these processes with identical rank orders of effectiveness. This indicates a common molecular basis for the disparate set of observed effects of IAPP.

show abstract

Section: Resultsmentioning

confidence: 99%

Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

Kumar

Schlamadinger

Brown

et al. 2015

Chemistry & Biology

100

View full text Add to dashboard Cite

show abstract

“…4,13,21 In this study we chose to investigate the effects of the targeted library of mimics 16-20 purely in the presence of a lipid bilayer, to assess their in vitro inhibition of amyloid formation ( Fig. 2A).…”

Section: A-helix Mimeticsmentioning

confidence: 99%

Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Kulikov

Kumar

Magzoub

et al. 2015

Tetrahedron Letters

Self Cite

View full text Add to dashboard Cite

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 ...

show abstract

“…20−24 Some of these compounds have been reported also to inhibit IAPP cytotoxicity and to prevent amyloidogenicity and/or cytotoxicity by other amyloidogenic proteins. 23,25 The second class includes synthetic, IAPP-derived peptides based on the concept of self-recognition. These peptides may be derivatives of full-length IAPP 26,27 or comprise IAPP segments.…”

mentioning

confidence: 99%

Molecular Tweezers Inhibit Islet Amyloid Polypeptide Assembly and Toxicity by a New Mechanism

Lopes¹,

Attar²,

Nair³

et al. 2015

ACS Chem. Biol.

View full text Add to dashboard Cite

In type-2 diabetes (T2D), islet amyloid polypeptide (IAPP) self-associates into toxic assemblies causing islet β-cell death. Therefore, preventing IAPP toxicity is a promising therapeutic strategy for T2D. The molecular tweezer CLR01 is a supramolecular tool for selective complexation of K residues in (poly)peptides. Surprisingly, it inhibits IAPP aggregation at substoichiometric concentrations even though IAPP has only one K residue at position 1, whereas efficient inhibition of IAPP toxicity requires excess CLR01. The basis for this peculiar behavior is not clear. Here, a combination of biochemical, biophysical, spectroscopic, and computational methods reveals a detailed mechanistic picture of the unique dual inhibition mechanism for CLR01. At low concentrations, CLR01 binds to K1, presumably nucleating nonamyloidogenic, yet toxic, structures, whereas excess CLR01 binds also to R11, leading to nontoxic structures. Encouragingly, the CLR01 concentrations needed for inhibition of IAPP toxicity are safe in vivo, supporting its development toward diseasemodifying therapy for T2D.

show abstract

Small molecule screening in context: Lipid‐catalyzed amyloid formation

Cited by 15 publications

References 39 publications

Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Molecular Tweezers Inhibit Islet Amyloid Polypeptide Assembly and Toxicity by a New Mechanism

Contact Info

Product

Resources

About