Preferred conformations of peptides containing α,α‐disubstituted α‐amino acids

Toniolo, Claudio; Bonora, Gian Maria; Bavoso, Alfonso; Benedetti, Ettore; Blasio, Benedetto Di; Pavone, Vincenzo; Pedone, Carlo

doi:10.1002/bip.360220129

Cited by 250 publications

(144 citation statements)

References 49 publications

(2 reference statements)

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“…The preponderance of C ␣ -disubstituted amino acid residues in compound 1 suggested a 3 10 -helix formation (15)(16)(17) for the first half of the peptide rather than an ␣-helix as found in compound 2 (5-7). Actually, despite the high Aib content in compound 1, the backbone conformations of compounds 1 and 2 are almost identical.…”

Section: Resultsmentioning

confidence: 85%

Crystal structure of the channel-forming polypeptide antiamoebin in a membrane-mimetic environment

Karle

Perozzo²,

Mishra³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Crystals of an ion-channel-forming peptaibol peptide in a partial membrane environment have been obtained by cocrystallizing antiamoebin with n-octanol. The antiamoebin molecule has a bent helical conformation very similar to that established for Leu-zervamicin, despite a significantly different sequence for residues 1-8. The bent helices assemble to form a polar channel in the shape of an hour glass that is quite comparable to that of Leu-zervamicin. Peptaibol antibiotics are attractive model systems for investigating the structure and function of membrane-channelforming polypeptides (1-3). Crystal structure determination of alamethicin (4) and Leu 1 -zervamicin (5-8) have provided details of the stereochemistry of these transmembrane helices and their models of association, leading to suggestions for plausible mechanisms of voltage gating (3-5). Thus far, crystal structures for these membrane-active peptides have been obtained without any cocrystallized lipid component. In this report, we describe the structure of an antiamoebin-octanol solvate at 1.0-Å resolution that reveals a membrane-mimetic environment for the peptaibol. Antiamoebins are a family of compounds closely related to 16-residue fungal polypeptides (9, 10) with anti-protozoal and anthelmintic activities (11).The sequence of antiamoebin 1 is compared with Leuzervamicin 2 and alamethicin 3, as follows (9): Ac-Phe-AibAib-Aib-Iva

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Section: Resultsmentioning

confidence: 85%

Crystal structure of the channel-forming polypeptide antiamoebin in a membrane-mimetic environment

Karle

Perozzo²,

Mishra³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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“…Ca-methyl-a-amino acids with well-defined stereo chemical properties impose local restrictions on backbone conformation, thus conferring structural stability (28)(29). Aib residue (a-amino isobutyric acid) is the prototype of Ca-methyl-a-amino acids, and is well known to be characterized by a restricted conformational freedom (30) in the 3 10 -a-helical region of the Ramachandran plot. Other Ca-methyl-a-amino acids, including Ca-methyl-phenylalanine (31) are b-turn and helix inducers, much stronger than the unmethylated, phenyl-containing, protein amino acid Phe.…”

Section: Development and Synthesis Of Rerf Analoguesmentioning

confidence: 99%

UPARANT: A Urokinase Receptor–Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency

Carriero

Bifulco²,

Minopoli

et al. 2014

Molecular Cancer Therapeutics

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This work is based on previous evidence showing that chemotactic sequence of the urokinase receptor (uPAR [88][89][90][91][92] ) drives angiogenesis in vitro and in vivo in a protease-independent manner, and that the peptide AcArg-Glu-Arg-Phe-NH 2 (RERF) prevents both uPAR 88-92 -and VEGF-induced angiogenesis. New N-acetylated and C-amidated peptide analogues containing a-methyl a-amino acids were designed and synthesized to optimize the biochemical properties for therapeutic applications. Among these, Ac-L-Arg-Aib-L-Arg-D-Ca(Me) Phe-NH 2 , named UPARANT, adopts in solution a turned conformation similar to that found for RERF, is stable to sterilization in 3 mg/mL sealed vials in autoclave for 20 minutes at 120 C, is stable in blood, and displays a long-time resistance to enzymatic proteolysis. UPARANT competes with N-formyl-Met-Leu-Phe (fMLF) for binding to the formyl-peptide receptor, inhibits VEGF-directed endothelial cell migration, and prevents cytoskeletal organization and avb3 activation in endothelial cells exposed to VEGF. In vitro, UPARANT inhibits VEGF-dependent tube formation of endothelial cells at a 100Â lower concentration than RERF. In vivo, UPARANT reduces to the basal level VEGF-dependent capillary sprouts originating from the host vessels that invaded Matrigel sponges implanted in mice, and completely prevents neovascularization induced by subcorneal implantation of pellets containing VEGF in rabbits. Both excellent stability and potency position UPARANT as a promising new therapeutic agent for the control of diseases fueled by excessive angiogenesis, such as cancer and inflammation.

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“…Linear peptides form fl-sheets (Karle, Karle, Mastropaolo, Camerman & Camerman, 1983), 3,0-helices for short peptides (Toniolo et al, 1983), ahelices for longer peptides Fox & Richards, 1982), double helices (Benedetti, di Blasio, Pedone, Lorenzi, Tomasic & Gramlich, 1979;Langs, 1988) and mixed helices consisting of a 3,0/ahelix and a fl-ribbon twisted into a helix (Karle, Flippen-Anderson, Sukumar & Balaram, 1987;Karle, Flippen-Anderson, Agarwalla & Balaram, 1991). The latter has been established in Leu-zervamicin and a 16-residue apolar analog that contain in their sequences three Pro or Hyp (hydroxyproline) residues at positions 10, 13 and 15.…”

Section: Backbonesmentioning

confidence: 99%

Folding, aggregation and molecular recognition in peptides

Karle¹

1992

Acta Crystallogr Sect B

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In past years, most of the X-ray structure determinations of oligopeptides were for cyclic peptides or for short linear peptides. Longer peptides usually presented many difficulties in obtaining suitable crystals since the molecules are intrinsically very flexible. More recently, it has been appreciated that the aminoisobutyric acid residue (Aib), which occurs naturally in many peptides of microbial origin, initiates helix folding. Several score of 7-to 15-residue linear peptides containing Aib have been synthesized, crystallized and had their structures determined to high resolution. Many of the peptide structures have been determined in more than one crystalline form. These peptide structures have yielded a plethora of information on types of helices, modes of hydration, water penetration into helical backbones, helices bent by Pro residues, parallel and antiparallel association of helices, effects of Leu residues on association of peptides, an example of a zipper assembly by side chains, and an example of a possible ion channel with a gating mechanism.

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Preferred conformations of peptides containing α,α‐disubstituted α‐amino acids

Cited by 250 publications

References 49 publications

Crystal structure of the channel-forming polypeptide antiamoebin in a membrane-mimetic environment

Crystal structure of the channel-forming polypeptide antiamoebin in a membrane-mimetic environment

UPARANT: A Urokinase Receptor–Derived Peptide Inhibitor of VEGF-Driven Angiogenesis with Enhanced Stability and In Vitro and In Vivo Potency

Folding, aggregation and molecular recognition in peptides

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