Peptides As Therapeutics with Enhanced Bioactivity

Goodwin, Daryn; Simerská, Pavla; Tóth, István

doi:10.2174/092986712803251548

Cited by 151 publications

(109 citation statements)

References 141 publications

(113 reference statements)

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“…Minimal similarity with the candidate peptide drug amino-acetylation and carboxy amidation [8,19]. Blocking of the endgroups by acetyl and amide groups has been shown to extend the invivo half-life of synthetic peptides by several folds.…”

Section: Cyclization Stabilize Structurementioning

confidence: 99%

“…Blocking of the endgroups by acetyl and amide groups has been shown to extend the invivo half-life of synthetic peptides by several folds. Additionally, amino terminal acetylation presumably increases the peptide lipophilicity enhancing the membrane permeability and passage across the intestinal or blood brain barrier [8,16,19]. An acetate salt of a peptide analog of the gonadotropin releasing hormone (GnRH) acts as a potent inhibitor of gonadotropin secretion and has diverse clinical applications [20].…”

Section: Cyclization Stabilize Structurementioning

confidence: 99%

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Interface Peptide Mimetics-Rationale and Application as Therapeutic Agents

Srinivasan¹

2016

Med chem

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Biomolecular recognition via protein-protein interactions (PPI) is central to the signaling events in most physiological and pathological processes. Hence PPI are considered excellent targets for drug development. In recent years there is considerable interest in the design and development of peptide based drugs as antagonists or agonists of PPI. High potency, great selectivity and better safety profile are significant advantages of peptide therapeutics. The following is a brief review of the rationale and modifications in the design of peptide mimetics of PPI interface.

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Section: Cyclization Stabilize Structurementioning

confidence: 99%

Section: Cyclization Stabilize Structurementioning

confidence: 99%

Interface Peptide Mimetics-Rationale and Application as Therapeutic Agents

Srinivasan¹

2016

Med chem

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“…Peptides are also much less costly compared with monoclonal antibodies that are large protein ligands, 15) because peptides can be readily prepared on a large scale with progress in chemical synthesis methods. 16) Therefore, peptides are expected to be effective, selective ligands for disease treatment.…”

Section: Introductionmentioning

confidence: 99%

Peptide-Based Cancer-Targeted DDS and Molecular Imaging

2017

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Targeting cancer cell-surface receptors is an attractive approach for cancer treatment and diagnosis. Peptides having high binding affinities to receptors overexpressed in cancer cells are useful because of their simple structure, low immunogenicity, and easy, cost-effective chemical synthesis. A number of peptide ligands have been developed for cancer cell-surface receptors and applied to nanoparticles with anticancer drugs, genes, small interfering RNAs (siRNAs), and molecular imaging agents. In particular, recent findings have revealed that peptide-modified PEGylated liposome-encapsulated drugs are effective in cancer-targeted therapy and cancer cell-specific imaging. This review discusses peptide-modified nanoparticles for drug delivery systems (DDS) and molecular imaging, focusing on peptide ligands for somatostatin receptors, integrin, transferrin receptor, human epidermal growth factor 2 (HER2), etc. In addition, methods to improve binding affinity or endosomal escape with spacer peptides and stimuli (internal and external) are discussed.

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“…The p27 negative regulator protein interferes the CDK2/cyclin A complex phosphorylation with elongation factor (E2F) and sensitizes the cells into apoptosis [39]. The most conserved cyclin groove recognition motif (CRM) of p27 has "Leu-Phe-Gly" (LFG) residues that involve the primary anchoring at Ile213, Leu214, Trp217, Arg250, Leu253, and Gln254 residues of cyclin A [18]. The studies on CDK2 enzyme inhibition illustrated the CRM region-derived acetyl-capped Arg-Lys-Leu-Phe-Gly (penta peptide, RKLFG) sequence which significantly restricts the CDK2 complex activity even at low micromolar range [2].…”

Section: Introductionmentioning

confidence: 99%

“…But, the peptide inhibitors have two main obstacles: (i) the intracellular protein-degrading enzymes easily degrade the peptides before target binding and (ii) they slow down the lipid bilayer penetration of the cell membrane [15]. Hence, unnatural amino acid groups are incorporated into the peptides which develop into peptidomimetics that improve the penetration ability and stability [18].…”

Section: Introductionmentioning

confidence: 99%

Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27KIP1-derived peptidomimetic inhibitors

Arumugasamy

Tripathi

Shanmugam³

et al. 2014

J Chem Biol

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Functionally activated cyclin-dependent kinase 2 (CDK2)/cyclin A complex has been validated as an interesting therapeutic target to develop the efficient antineoplastic drug based on the cell cycle arrest. Cyclin A binds to CDK2 and activates the kinases as well as recruits the substrate and inhibitors using a hydrophobic cyclin-binding groove (CBG). Blocking the cyclin substrate recruitment on CBG is an alternative approach to override the specificity hurdle of the currently available ATP site targeting CDK2 inhibitors. Greater understanding of the interaction of CDK2/cyclin A complex with p27 (negative regulator) reveals that the LeuPhe-Gly (LFG) motif region of p27 binds with the CBG site of cyclin A to arrest the malignant cell proliferation that induces apoptosis. In the present study, Replacement with Partial Ligand Alternatives through Computational Enrichment (REPLACE) drug design strategies have been applied to acquire LFG peptide-derived peptidomimetics library. The peptidomimetics function is equivalent with respect to substrate p27 protein fashion but does not act as an ATP antagonist. The combined approach of molecular docking, molecular dynamics (MD), and molecular electrostatic potential and ADME/T prediction were carried out to evaluate the peptidomimetics. Resultant interaction and electrostatic potential maps suggested that smaller substituent is desirable at the position of phenyl ring to interact with Trp217, Arg250, and Gln254 residues in the active site. The best docked poses were refined by the MD simulations which resulted in conformational changes. After equilibration, the structure of the peptidomimetic and receptor complex was stable. The results revealed that the various substrate protein-derived peptidomimetics could serve as perfect leads against CDK2 protein.

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Peptides As Therapeutics with Enhanced Bioactivity

Cited by 151 publications

References 141 publications

Interface Peptide Mimetics-Rationale and Application as Therapeutic Agents

Interface Peptide Mimetics-Rationale and Application as Therapeutic Agents

Peptide-Based Cancer-Targeted DDS and Molecular Imaging

Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27KIP1-derived peptidomimetic inhibitors

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