Amide‐to‐Ester Substitution Allows Fine‐Tuning of the Cyclopeptide Conformational Ensemble

Cupido, Tommaso; Spengler, Jan; Ruiz-Rodríguez, Javier; Adán, Jaume; Mitjans, Francesc; Piulats, Jaume; Alberício, Fernando

doi:10.1002/ange.200907274

Cited by 9 publications

(3 citation statements)

References 38 publications

(15 reference statements)

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“…The FESs of c(‐RGDf(NMe)V‐) and CDGRC indicate that more than 90 % of the structures are contained in the β L and α L regions, respectively, whereas CisoDGRC populates the three isoenergetic regions β L , β P , and α (Table 1). Interestingly, in the β L minimum, the Gly ϕ and ψ angles of c(‐RGDf(NMe)V‐) structures are similar to those observed for the cyclopeptide bound to the αvβ3 receptor (Table 1), which is consistent with the fact that the amide groups of Gly and the following residue point in opposite directions 26–28. In contrast, in CDGRC this alternate conformation is not fulfilled, which contributes to its inability to bind αvβ3 25.…”

Section: Population Distribution and Energetic And Geometric Charactesupporting

confidence: 77%

Use of Metadynamics in the Design of isoDGR‐Based αvβ3 Antagonists To Fine‐Tune the Conformational Ensemble

et al. 2011

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The integrin family of cell-adhesion receptors regulates cellular functions crucial to the initiation, progression, and metastasis of solid tumors. In particular, integrin avb3 plays a key role in endothelial cell survival and migration during tumor angiogenesis.[1] It is therefore gaining increasing importance as a drug target in antiangiogenic cancer therapy. [2,3] The sequence Arg-Gly-Asp (RGD), which is contained in natural avb3 interactors, such as vitronectin, fibronectin, fibrinogen, osteopontin, and tenascin, is by far the most prominent ligand to promote specific cell adhesion through stimulation. This sequence is therefore attractive as a lead for the development of different integrin antagonists. [4] Recent biochemical studies showed that deamidation of the NGR sequence gives rise to isoDGR, a new avb3-binding motif.[5] This sequence constitutes a novel class of peptidic integrin ligands and paves the way to drug-design studies with a focus on the synthesis and characterization of a new generation of isoDGR-based macrocycles. [6,7] For the design of low-molecular-mass isoDGR-containing molecules, an accurate determination of their biologically active conformation is a prerequisite. The presence of the b bond induces high flexibility in isoDGR-containing macrocycles and thus augments the range of accessible interconverting conformations.[8] However, the identification of relevant conformations that might affect binding affinity is challenging for standard spectroscopic and diffraction techniques. Atomistic simulations, such as molecular dynamics (MD), replica-exchange molecular dynamics (REMD), and Monte Carlo (MC) simulations, can complement experimental data.[9, 10] However, they often fail to generate reliable equilibrium conformations because of the rugged and complex nature of the free-energy surface (FES) that is accessible to the system. As a consequence, computational sampling is often relegated to some local, unrealistic minima, which compromise subsequent docking studies. As computational drug design becomes increasingly reliant on virtual screening and on high-throughput 3D modeling, the need for fast and accurate computational methods for sampling of the ensemble of energetically accessible conformations is warranted. In this context, several techniques, including the local-elevation method, [11] taboo search, [12] the Wang-Landau method, [13] adaptive force bias, [14] conformational flooding, [15] umbrella sampling, [16] weighted histogram techniques, [17] transitionstate theory, and path sampling, [18] have been developed to address the sampling problem, through either reconstruction of the free energy or the direct acceleration of events that might happen on a long timescale ("rare events"). Related to these methods, metadynamics (MetaD) [19,20] has emerged as a powerful coarse-grained non-Markovian molecular-dynamics approach for the acceleration of rare events and the efficient and rapid computation of multidimensional free-energy surfaces as a function of a restricted number of degrees...

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Section: Population Distribution and Energetic And Geometric Charactesupporting

confidence: 77%

Use of Metadynamics in the Design of isoDGR‐Based αvβ3 Antagonists To Fine‐Tune the Conformational Ensemble

et al. 2011

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“…) with ester link between N ‐Val and Arg showed increased potency with respect to the parent compound, being a potent small‐molecule dual αvβ3 and αvβ5 antagonist in cell adhesion assays, IC 50 αvβ3/FN = 1.0 × 10 −7 M, IC 50 αvβ5/VN = 6.0 × 10 −8 M, respectively, compared to IC 50 = 3.2 × 10 −7 and 2.0 × 10 −7 M for cilengitide under the same conditions. As another example, the N ‐Me group was replaced by N ‐oligoethylene glycol (N‐OEG) of increasing length to provide the more lipophilic bioactive analogs 6 (Fig. ) …”

Section: Integrins and Their Ligandsmentioning

confidence: 99%

Integrin Ligands with α/β‐Hybrid Peptide Structure: Design, Bioactivity, and Conformational Aspects

Marco

Tolomelli

Juaristi

et al. 2016

Medicinal Research Reviews

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Integrins are cell surface receptors for proteins of the extracellular matrix and plasma-borne adhesive proteins. Their involvement in diverse pathologies prompted medicinal chemists to develop small-molecule antagonists, and very often such molecules are peptidomimetics designed on the basis of the short native ligand-integrin recognition motifs. This review deals with peptidomimetic integrin ligands composed of α- and β-amino acids. The roles exerted by the β-amino acid components are discussed in terms of biological activity, bioavailability, and selectivity. Special attention is paid to the synthetic accessibility and efficiency of conformationally constrained heterocyclic scaffolds incorporating α/β-amino acid span.

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“…[15][16][17] A previous report about conformational studies of a cyclic RGD peptide showed that peptides with amide-to-ester substitutions can form similar conformations with original peptides. 18 Another report showed that a reverse ester-toamide substitution on the backbone of a bioactive peptide did not affect its inhibitory activity in vitro, but significantly reduced its inhibitory activity in cells, 19 indirectly suggesting that the ester-to-amide substitution reduces the membrane permeability of this peptide. Considering these reports, amide-to-4 ester substitution of a proper amide bond is expected to improve the passive membrane permeability of a peptide and, at the same time, allow the modified peptide to form similar conformations with the original peptide.…”

Section: Introductionmentioning

confidence: 99%

Amide-to-Ester Substitution Improves Membrane Permeability of a Cyclic Peptide Without Altering Its Three-Dimensional Structure

Hosono¹,

Morimoto²,

Townsend³

et al. 2020

Preprint

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<div> <div> <div> <p>Cyclic peptides are attractive molecules as inhibitors with high affinity and selectivity against intracellular protein-protein interactions (PPIs). On the other hand, cyclic peptides generally have low passive cell-membrane permeability, which makes it difficult to discover cyclic peptides that efficiently permeate into cells and inhibit intracellular PPIs. Here, we show that backbone amide-to-ester substitutions are useful for improving membrane permeability of peptides. Permeability in a series of model dipeptides increased upon amide-to-ester substitution. Amide-to-ester substitutions increased permeability in the same manner as amide-to-N-methyl amide substitutions, which are conventionally used for increasing permeability. Furthermore, amide-to-ester substitutions of exposed amides of a cyclic peptide successfully improved permeability. Conformational studies of the cyclic peptides using NMR and molecular mechanics calculations revealed that an amide-to-ester substitution of an exposed amide bond did not affect its low-energy conformation in CDCl<sub>3</sub>, in contrast with an N-methyl amide substitution. We envision that amide-to-ester substitution will be a potentially useful strategy for rational design of bioactive peptides with high membrane permeability. </p> </div> </div> </div>

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Amide‐to‐Ester Substitution Allows Fine‐Tuning of the Cyclopeptide Conformational Ensemble

Abstract: Supporting information for this article (experimental details of cyclodepsipeptide syntheses, cellular assays, structure analysis and calculations, characterization of compounds, and MD calculations) is available on the WWW under http://dx.

Cited by 9 publications

References 38 publications

Use of Metadynamics in the Design of isoDGR‐Based αvβ3 Antagonists To Fine‐Tune the Conformational Ensemble

Use of Metadynamics in the Design of isoDGR‐Based αvβ3 Antagonists To Fine‐Tune the Conformational Ensemble

Integrin Ligands with α/β‐Hybrid Peptide Structure: Design, Bioactivity, and Conformational Aspects

Amide-to-Ester Substitution Improves Membrane Permeability of a Cyclic Peptide Without Altering Its Three-Dimensional Structure

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