Concepts and progress in the development of peptide mimetics

Gl, Olson; Dr, Bolin; Mp, Bonner; M, Bös; Cook, Colleen-M.; Dc, Fry; Bj, Graves; Hatada, Marcos; De, Hill; Kahn, Michaël

doi:10.1021/jm00073a001

Cited by 259 publications

(58 citation statements)

References 8 publications

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“…In fact, previous structure-activity studies suggested that the central part of the peptide behaves more like a molecular spacer responsible for positioning the N-and C-domains and might not be involved directly in the interaction with the PAC1 receptor. Such a hypothesis has already been proposed for other members of the VIP-glucagon-GHRF-secretin superfamily (Olson et al 1993). To evaluate this postulate, a library of eight hybrid peptides containing an aliphatic flexible molecular spacer connecting the N-terminal disordered domain to the helical C-terminal region was designed.…”

Section: Discussionmentioning

confidence: 64%

Biological and Structural Analysis of Truncated Analogs of PACAP27

et al. 2008

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The affinity toward the PAC1 receptor, the biological activity, and the alpha-helical content of several truncated PACAP27 analogs were measured. We first evaluated the pharmacological and structural parameters of C-terminal shortened PACAP fragments, from PACAP(1-23) to PACAP(1-19). All carboxy-truncated derivatives demonstrated circular dichroism spectra typical of a helical conformation. On the other hand, progressive shortening of the C-terminal domain gradually decreases the potency of PACAP to bind and to activate the PAC1 receptor. This decrease in biological activity was mainly attributed to the removal of residues that seem to interact directly with the receptor rather than to a destabilization of the C-terminal helical conformation. We also investigated the pharmacological and conformational characteristics of several hybrid PACAP27 derivatives containing an aliphatic molecular spacer connecting the N-terminal domain to the C-terminal region. However, this strategy revealed that none of these discontinuous analogs showed any significant affinity toward the PAC1 receptor, even if some of them exhibited circular dichroism spectra corresponding to an alpha-helical structure. This study suggests that several domains of PACAP27 are involved in the interaction with the PAC1 receptor and that the presence of the helical conformation is not a sufficient feature for receptor activation.

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Section: Discussionmentioning

confidence: 64%

Biological and Structural Analysis of Truncated Analogs of PACAP27

et al. 2008

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“…Longer templates and particularly templates which specifically address 3-D-vectorial positioning of termini are much less common. Notable examples before 1994 are cited in an excellent review by Olsen et al (92), and more recent examples are due to Robinson (82,88,93), Schreiber (94), and Chmielewski (95). It is of course important also to consider the degree of flexibility afforded by a potential template.…”

Section: Structure-based Design Of Antiallergic Drugsmentioning

confidence: 99%

Peptide blocking of IgE/receptor interaction: possibilities and pitfalls

Helm

Spivey

Padlan

1997

Allergy

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“…Actually, we affirmed that the designed peptides can bind to human profilins (K89, T91 or T96) in the docking simulation (data not shown). Although this crossreaction would be attributed to conformational flexibility of the peptide, the affinity or specificity can be ameliorated by constraining the conformational flexibility in the peptidomimetics approach (Olson et al, 1993). The penetration problem could be solved by attaching a cell penetrating peptide, such as a Tat-peptide (Henriques et al, 2006;Park et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Target validation and ligand development for a pathogenic fungal profilin, using a knock‐down strain of pathogenic yeast Candida glabrata and structure‐based ligand design

Ueno

Tsutsumi

Chibana

2010

Yeast

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The emergence of antifungal drug resistance is triggering vigorous searches for novel antifungal targets and lead compounds. In this study, we focused on fungal profilin, which is a small actin control protein sharing limited homology to human profilin. To validate its potentiality as a target, a profilin-conditional mutant of the pathogenic yeast Candida glabrata was constructed, using a regulatable Tet promoter, and its growth was monitored in vitro. Repression of profilin expression led to severe growth defect, demonstrating the potential of this protein as a novel antifungal target. Next, novel peptides binding to the active interface of profilin were designed by computer simulation. ELISA analysis showed that these peptides did bind to the wild-type profilin but bound less strongly to a profilin with amino acid substitutions at the active interface. Hence, we show here that profilin is a potential antifungal target and offer novel peptide ligands.

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Concepts and progress in the development of peptide mimetics

Cited by 259 publications

References 8 publications

Biological and Structural Analysis of Truncated Analogs of PACAP27

Biological and Structural Analysis of Truncated Analogs of PACAP27

Peptide blocking of IgE/receptor interaction: possibilities and pitfalls

Target validation and ligand development for a pathogenic fungal profilin, using a knock‐down strain of pathogenic yeast Candida glabrata and structure‐based ligand design

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