Pseudo-A(1,3) Strain as a Key Conformational Control Element in the Design of Poly-<scp>l</scp>-proline Type II Peptide Mimics

Zhang, Rui; Brownewell, Floyd E.; Madalengoitia, José S.

doi:10.1021/ja972494e

Cited by 50 publications

(31 citation statements)

References 20 publications

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“…This could have major consequences for drug design, because it allows a search for novel functionalities to replace the proline that can interact with new regions of the SH3 and hence enhance binding. Novel oligomers containing proline analogs have been observed to adopt a PP II conformation (131,132). It also appears to be possible to replace proline by other N-substituted amino acids.…”

Section: Polyproline Peptidomimeticsmentioning

confidence: 99%

The importance of being proline: the interaction of proline‐rich motifs in signaling proteins with their cognate domains

2000

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Acommon focus among molecular and cellular biologists is the identification of proteins that interact with each other. Yeast two-hybrid, cDNA expression library screening, and coimmunoprecipitation experiments are powerful methods for identifying novel proteins that bind to one's favorite protein for the purpose of learning more regarding its cellular function. These same techniques, coupled with truncation and mutagenesis experiments, have been used to define the region of interaction between pairs of proteins. One conclusion from this work is that many interactions occur over short regions, often less than 10 amino acids in length within one protein. For example, mapping studies and 3-dimensional analyses of antigen-antibody interactions have revealed that epitopes are typically 4-7 residues long (1). Other examples include protein-interaction modules, such as Src homology (SH) 2 and 3 domains, phosphotyrosine binding domains (PTB), postsynaptic density/disc-large/ZO1 (PDZ) domains, WW domains, Eps15 homology (EH) domains, and 14-3-3 proteins that typically recognize linear regions of 3-9 amino acids. Each of these domains has been the subject of recent reviews published elsewhere (2 3 4 5 6 7). Among the primary structures of many ligands for protein-protein interactions, the amino acid proline is critical. In particular, SH3, WW, and several new protein-interaction domains prefer ligand sequences that are proline-rich. In addition, even though ligands for EH domains and 14-3-3 domains are not proline-rich, they do include a single proline residue. This review highlights the analysis of those protein-protein interactions that involve proline residues, the biochemistry of proline, and current drug discovery efforts based on proline peptidomimetics.-Kay, B. K., Williamson, M. P., Sudol, M. The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains.

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Section: Polyproline Peptidomimeticsmentioning

confidence: 99%

The importance of being proline: the interaction of proline‐rich motifs in signaling proteins with their cognate domains

2000

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“…The effect of the proline residue on peptide conformation1–3 has been the impetus for the design of various unnatural substituted prolines. These amino acid surrogates have featured in a number of biologically active4–7 and highly ordered peptides 8, 9. Prolines substituted at the 4‐position have been shown to enhance the thermal stability of collagen‐mimetic triple helices, with trans‐ 4‐fluoroproline yielding the most striking results 10–12.…”

Section: Methodsmentioning

confidence: 99%

Stereoselective Synthesis of Boc-Protectedcisandtrans-4-Trifluoromethylprolines by Asymmetric Hydrogenation Reactions

Valle¹,

Goodman²

2002

Angew. Chem.

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The effect of the proline residue on peptide conformation [1±3] has been the impetus for the design of various unnatural substituted prolines. These amino acid surrogates have featured in a number of biologically active [4±7] and highly ordered peptides. [8,9] Prolines substituted at the 4-position have been shown to enhance the thermal stability of collagenmimetic triple helices, with trans-4-fluoroproline yielding the most striking results. [10±12] The nature of the functional group and the steric constraints imposed by the C4 substituent can greatly influence the conformation of the pyrrolidine ring, as well as the rate of cis ± trans isomerization about the amide bond. [13±15] For these reasons, the preparation of 4-substituted prolines is an attractive goal in peptidomimetic chemistry.The synthesis of cis-4-phenylproline by a hydrogenolysis reaction, which starts from hydroxyproline was recently described by Hruby and co-workers. [16] In addition, Nevalainen et al. reported a preparation of Fmoc-trans-4-methylproline (Fmoc 9-fluorenylmethoxycarbonyl) by asymmetric hydrogenation, which yields the desired isomer in a 6:1 diastereomeric ratio before purification. [17] Although these and other syntheses of 4-substituted prolines are in the literature, [18±21] a number of desirable targets continue to pose a synthetic challenge. In particular, several trans-substituted prolines have been difficult to synthesize with high stereo-selectivity. In connection with our studies on bioactive and highly ordered peptides, we undertook the synthesis of both stereoisomers of 4-trifluoromethyl-l-proline. These building blocks are expected to have profound conformational effects on their host structures, which arise from the electronegative nature of the trifluoromethyl group.Our strategy for the preparation of the title compounds employs asymmetric hydrogenation of the pyrrolines shown in Scheme 1. For the synthesis of the cis isomer, the facial A B cis isomer trans isomer Scheme 1. Strategies for the asymmetric hydrogenation of pyrroline intermediates. A Sterically directed hydrogenation, B hydroxy-directed hydrogenation.selectivity of the hydrogenation was expected to depend on steric factors, which result from protection of the hydroxy functionality as an ether or ester moiety. We were unable to find previous syntheses of trans-substituted prolines that exploit the potential for hydroxy-directed hydrogenation of pyrroline intermediates. We envisioned this as a viable route towards the trans-proline isomer as well as related analogues.The retrosynthesis in Scheme 2 shows Boc-4-prolinone (Boc tert-butoxycarbonyl) as a precursor to the desired pyrrolines. N CH 2 OR 1 F 3 C Boc N O CO 2 CH 3 Boc R 1 = H, or PG 2 Hyp-OMeScheme 2. Retrosynthesis of Boc-4-trifluormethyl-l-proline; Hyp hydroxyproline.The synthesis of Boc-4-trifluoromethyl-l-proline (Scheme 3) begins with the methyl ester of commercially available and inexpensive trans-4-hydroxyproline (1). Bocprotection was carried out under normal conditions, followed by oxi...

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“…It is easy here to identify a subgroup with a -PO-group instead of -CO-in peptides (Bone et al 1991, Fraser et al 1992, Tsukamoto et al 1998, Collinsova and Jiracek 2000, Demange et al 2002, Grembecka et al 2003, and -SO 2 - (Langenhan et al 2001). There is a subgroup with a fluorine atom bound to a carbon atom (Thaisrivongs et al 1986, Fraser et al 1992, Silva et al 1996, Volonterio et al 2003, Annedi et al 2005, Xiao et al 2005 and a subgroup where a carbon-carbon double bond substitutes a C-N bond in peptide linkage (Lehman de Gaeta and Czarniecki 1989, Jaskolski et al 1991, Gardner et al 1995, Zhang et al 1998, Xiao et al 2005. There is also the set with a carbonyl group in a peptide linkage reduced to a hydroxyl group (Kempf et al 1990, Jaskolski et al 1991.…”

Section: From Peptide To Small Molecule Leadmentioning

confidence: 99%

Modelling of potentially promising SARS protease inhibitors

Plewczynski

Hoffmann

Grotthuss

et al. 2007

J. Phys.: Condens. Matter

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In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation.

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Pseudo-A(1,3) Strain as a Key Conformational Control Element in the Design of Poly-l-proline Type II Peptide Mimics

Cited by 50 publications

References 20 publications

The importance of being proline: the interaction of proline‐rich motifs in signaling proteins with their cognate domains

The importance of being proline: the interaction of proline‐rich motifs in signaling proteins with their cognate domains

Stereoselective Synthesis of Boc-Protectedcisandtrans-4-Trifluoromethylprolines by Asymmetric Hydrogenation Reactions

Modelling of potentially promising SARS protease inhibitors

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