Use of Steric Interactions To Control Peptide Turn Geometry. Synthesis of Type VI β-Turn Mimics with 5-<i>tert</i>-Butylproline

Halab, Liliane; Lubell, William D.

doi:10.1021/jo990294a

Cited by 93 publications

(79 citation statements)

References 67 publications

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“…The proline residue appears to have a key role in AngII structure stabilization as this was the only b-substitution which resulted in CD spectra indicative of random coil conformation. The importance of this proline residue is most likely due to its ability to adopt cis peptide bonds and as a consequence induce tight turn structures (Halab and Lubell, 1999;Halab et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

β‐amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)

Clayton

Hanchapola

Hausler

et al. 2011

J of Molecular Recognition

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In spite of the important role of angiotensin converting enzyme 2 (ACE2) in the cardiovascular system, little is known about the substrate structural requirements of the AngII-ACE2 interaction. Here we investigate how changes in angiotensin II (AngII) structure affect binding and cleavage by ACE2. A series of C3 β-amino acid AngII analogs were generated and their secondary structure, ACE2 inhibition, and proteolytic stability assessed by circular dichroism (CD), quenched fluorescence substrate (QFS) assay, and LC-MS analysis, respectively. The β-amino acid-substituted AngII analogs showed differences in secondary structure, ACE2 binding and proteolytic stability. In particular, three different subsets of structure-activity profiles were observed corresponding to substitutions in the N-terminus, the central region and the C-terminal region of AngII. The results show that β-substitution can dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage. β-amino acid substitution in the N-terminal region of AngII caused little change in structure or substrate cleavage, while substitution in the central region of AngII lead to increased β-turn structure and enhanced substrate cleavage. β-amino acid substitution in the C-terminal region significantly diminished both secondary structure and proteolytic processing by ACE2. The β-AngII analogs with enhanced or decreased proteolytic stability have potential application for therapeutic intervention in cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

β‐amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)

Clayton

Hanchapola

Hausler

et al. 2011

J of Molecular Recognition

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“…b-turns are an important recognition element of peptides and proteins, and a great deal of scientific effort has been applied to classifying, designing and synthesizing b-turn mimetics [15,[33][34][35][36][37][38][39][40][41][42][43]. However, the traditional classification of b-turns is based on backbone criterion, which has little reflection on the position of the important recognition elements, the side chains.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the importance of side chain spatial arrangements in molecular recognition, b-turns are currently classified into nine types based on the main chain dihedral angles, /2, w2, /3 and w3 [2,[29][30][31][32]. Although this classification of b-turns has been extremely useful and has been used widely to design peptidomimetics [15,[33][34][35][36][37][38][39][40][41][42][43], it makes very little functional sense, as it is not side-chain based. In addition, and as we will illustrate, each type of b-turn in the current classification can have two or more clusters of side chain spatial arrangements and different types of ''classical'' b-turns can have the same side chain spatial arrangement.…”

mentioning

confidence: 99%

Topological side-chain classification of β-turns: Ideal motifs for peptidomimetic development

Tran¹,

McKie

Meutermans

et al. 2005

J Comput Aided Mol Des

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Beta-turns are important topological motifs for biological recognition of proteins and peptides. Organic molecules that sample the side chain positions of beta-turns have shown broad binding capacity to multiple different receptors, for example benzodiazepines. Beta-turns have traditionally been classified into various types based on the backbone dihedral angles (phi2, psi2, phi3 and psi3). Indeed, 57-68% of beta-turns are currently classified into 8 different backbone families (Type I, Type II, Type I', Type II', Type VIII, Type VIa1, Type VIa2 and Type VIb and Type IV which represents unclassified beta-turns). Although this classification of beta-turns has been useful, the resulting beta-turn types are not ideal for the design of beta-turn mimetics as they do not reflect topological features of the recognition elements, the side chains. To overcome this, we have extracted beta-turns from a data set of non-homologous and high-resolution protein crystal structures. The side chain positions, as defined by C(alpha)-C(beta) vectors, of these turns have been clustered using the kth nearest neighbor clustering and filtered nearest centroid sorting algorithms. Nine clusters were obtained that cluster 90% of the data, and the average intra-cluster RMSD of the four C(alpha)-C(beta) vectors is 0.36. The nine clusters therefore represent the topology of the side chain scaffold architecture of the vast majority of beta-turns. The mean structures of the nine clusters are useful for the development of beta-turn mimetics and as biological descriptors for focusing combinatorial chemistry towards biologically relevant topological space.

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“…A great deal of scientific effort has been applied to classify, design and synthesize b-turn mimetics [47,[55][56][57][58][59][60][61][62][63][64][65][66][67][68]. To compare our clustering of loops with the traditional b-turn type classification as defined by Hutchinson and Thornton [69], the loops in the vector plots in Fig.…”

Section: Relationship Between the 39 Clustersmentioning

confidence: 99%

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

Tran

Kulis

Long

et al. 2010

J Comput Aided Mol Des

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Medicinal chemists synthesize arrays of molecules by attaching functional groups to scaffolds. There is evidence suggesting that some scaffolds yield biologically active molecules more than others, these are termed privileged substructures. One role of the scaffold is to present its side-chains for molecular recognition, and biologically relevant scaffolds may present side-chains in biologically relevant geometries or shapes. Since drug discovery is primarily focused on the discovery of compounds that bind to proteinaceous targets, we have been deciphering the scaffold shapes that are used for binding proteins as they reflect biologically relevant shapes. To decipher the scaffold architecture that is important for binding protein surfaces, we have analyzed the scaffold architecture of protein loops, which are defined in this context as continuous four residue segments of a protein chain that are not part of an α-helix or β-strand secondary structure. Loops are an important molecular recognition motif of proteins. We have found that 39 clusters reflect the scaffold architecture of 89% of the 23,331 loops in the dataset, with average intra-cluster and inter-cluster RMSD of 0.47 and 1.91, respectively. These protein loop scaffolds all have distinct shapes. We have used these 39 clusters that reflect the scaffold architecture of protein loops as biological descriptors. This involved generation of a small dataset of scaffold-based peptidomimetics. We found that peptidomimetic scaffolds with reported biological activities matched loop scaffold geometries and those peptidomimetic scaffolds with no reported biologically activities did not. This preliminary evidence suggests that organic scaffolds with tight matches to the preferred loop scaffolds of proteins, implies the likelihood of the scaffold to be biologically relevant.

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Use of Steric Interactions To Control Peptide Turn Geometry. Synthesis of Type VI β-Turn Mimics with 5-tert-Butylproline

Cited by 93 publications

References 67 publications

β‐amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)

β‐amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)

Topological side-chain classification of β-turns: Ideal motifs for peptidomimetic development

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

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