Computational design of peptide ligands

Vanhee, Peter; Sloot, Almer M. van der; Verschueren, Erik; Serrano, Luís; Rousseau, Frédéric; Schymkowitz, Joost

doi:10.1016/j.tibtech.2011.01.004

Cited by 145 publications

(116 citation statements)

References 73 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…A range of pathological disorders is related to peptide-protein interactions (Naider and Anglister, 2009), making them interesting leads for protein drug design. However, for rational design of peptidic drugs, a thorough understanding and atomistic structural knowledge of peptide-protein complexes is necessary (Rubinstein and Niv, 2009;Vanhee et al, 2011). A number of structures have been resolved experimentally and have provided important insight into the nature of peptide-mediated interactions (Diella et al, 2008;London et al, 2010;Petsalaki and Russell, 2008;Stein and Aloy, 2010).…”

Section: Introductionmentioning

confidence: 99%

Fully Blind Peptide-Protein Docking with pepATTRACT

2015

View full text Add to dashboard Cite

Peptide-protein interactions are ubiquitous in the cell and form an important part of the interactome. Computational docking methods can complement experimental characterization of these complexes, but current protocols are not applicable on the proteome scale. Here, we present a new fully blind flexible peptide-protein docking protocol, pepATTRACT, which combines a rapid coarse-grained global peptide docking search of the entire protein surface with a two-stage atomistic flexible refinement. Global unbound-unbound docking yielded near-native models for 70% of the docking cases when testing the protocol on the largest benchmark of peptide-protein complexes available to date. This performance is similar to that of state-of-the-art local docking protocols that rely on information about the binding site. Upon restricting the search to the peptide binding region, the resulting pepATTRACT-local approach outperformed existing methods. Docking scripts for pepATTRACT and pepATTRACT-local can be generated via a web interface at www.attract.ph.tum.de/peptide.html.

show abstract

Section: Introductionmentioning

confidence: 99%

Fully Blind Peptide-Protein Docking with pepATTRACT

2015

View full text Add to dashboard Cite

show abstract

“…2 Concomitantly, advances in structural biology, proteomics, and peptide library screening methodologies have expedited the design and discovery of short amino acid sequences capable of recapitulating the biological functions of the parent full-length proteins. [3][4][5] Toward tissue engineering and regenerative medicine applications, peptides have been engineered to mimic a vast range of growth factors, including vascular endothelial growth factor 6 (VEGF), platelet-derived growth factor 7 (PDGF), nerve growth factor, 8 brain-derived neurotrophic factor, 9 and epidermal growth factor. 10 Counteracting the therapeutic potential of peptide drugs is pharmacokinetic challenges associated with degradation, bioavailability, and metabolic clearance following administration.…”

Section: Introductionmentioning

confidence: 99%

Avidity-Controlled Delivery of Angiogenic Peptides from Injectable Molecular-Recognition Hydrogels

Mulyasasmita

Cai

Hori

et al. 2014

Tissue Engineering Part A

View full text Add to dashboard Cite

Peptide mimics of growth factors represent an emerging class of therapeutic drugs due to high biological specificity and relative ease of synthesis. However, maintaining efficacious therapeutic dosage at the therapy site has proven challenging owing to poor intestinal permeability and short circulating half-lives in the blood stream. In this work, we present the affinity immobilization and controlled release of QK, a vascular endothelial growth factor (VEGF) mimetic peptide, from an injectable mixing-induced two-component hydrogel (MITCH). The MITCH system is crosslinked by reversible interactions between WW domains and complementary proline-rich peptide modules. Fusion of the QK peptide to either one or two units of the proline-rich sequence creates bifunctional peptide conjugates capable of specific binding to MITCH while preserving their angiogenic bioactivity. Presenting two repeats of the proline-rich sequence increases the binding enthalpy 2.5 times due to avidity effects. Mixing of the drug conjugates with MITCH components results in drug encapsulation and extended release at rates consistent with the affinity immobilization strength. Human umbilical vein endothelial cells (HUVECs) treated with the soluble drug conjugates exhibit morphogenetic events of VEGF receptor 2 signal transduction followed by cell migration and organization into networks characteristic of early angiogenesis. In a three-dimensional model where HUVECs were cultured as spheroids in a matrix of collagen and fibronectin, injection of drug-releasing MITCH resulted in significantly more cell outgrowth than drugs injected in saline. This ability to sustain local drug availability is ideal for therapeutic angiogenesis applications, where spatiotemporal control over drug distribution is a key requirement for clinical success.

show abstract

“…Comprehensive biophysical and biochemical characterization of the binding molecules, confirmation of their target recognition abilities, and ideally the detailed atomic resolution of the binding interface is required [214] Molecules with moderate affinity to the target or with unfavorable characteristics (low solubility, aggregation, toxicity, etc) are subjected to several rounds of affinity maturation under conditions of increased stringency with special emphasis on selecting high stability compounds. This is usually carried out through random mutagenesis of variable regions (sometimes involving the scaffold), or by applying more focused approaches guided by rational computer aided design based on structural data and the results of comprehensive mutational scanning, generating heatmaps of antigen-binding enrichment ratios [166, 214-220]. Quite often maturation rounds are performed in different library screening settings and display methods used during primary selection rounds can be complemented by Y2H for affinity evolution.…”

Section: Selection Techniquesmentioning

confidence: 99%

“…The flexibility of PA platforms permits a variety of binding surfaces capable of accommodating large flat protein-protein interfaces as well as the clefts and pockets targeted by small molecules [220]. This fast growing class of antibody mimetics is finding its way into the field of biomedical and bioanalytical applications dominated by antibodies and nucleic acids aptamers.…”

Section: Applicationsmentioning

confidence: 99%

Peptide Aptamers: Development and Applications

Reverdatto¹,

Burz²,

Shekhtman

2015

CTMC

151

104

View full text Add to dashboard Cite

Peptide aptamers are small combinatorial proteins that are selected to bind to specific sites on their target molecules. Peptide aptamers consist of short, 5-20 amino acid residues long sequences, typically embedded as a loop within a stable protein scaffold. Various peptide aptamer scaffolds and in vitro and in vivo selection techniques are reviewed with emphasis on specific biomedical, bioimaging, and bioanalytical applications.

show abstract

Computational design of peptide ligands

Cited by 145 publications

References 73 publications

Fully Blind Peptide-Protein Docking with pepATTRACT

Fully Blind Peptide-Protein Docking with pepATTRACT

Avidity-Controlled Delivery of Angiogenic Peptides from Injectable Molecular-Recognition Hydrogels

Peptide Aptamers: Development and Applications

Contact Info

Product

Resources

About