From peptides to drugs via phage display

Kay, Brian K.; Kurakin, Alexei; Hyde-DeRuyscher, Robin

doi:10.1016/s1359-6446(98)01220-3

Cited by 76 publications

(61 citation statements)

References 92 publications

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“…It is believed that this method is more successful in identifying ligands against various proteins because the peptide ligands favor binding to recesses or cavities in the target proteins by displacing water molecules, and typically, such sites are biologically important (39). Our screening led to the identification of five peptide ligands against fB, but only one showed inhibition of fB activation at a high micromolar concentration (IC 50 = 56 mM) (Fig.…”

Section: Discussionmentioning

confidence: 98%

Identification of Complin, a Novel Complement Inhibitor that Targets Complement Proteins Factor B and C2

Kadam

Sahu

2010

The Journal of Immunology

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Complement factor B (fB) is a key constituent of the alternative pathway (AP). Its central role in causing inflammation and tissue injury through activation of the AP urges the need for its therapeutic targeting. In the current study, we have screened phage-displayed random peptide libraries against fB and identified a novel cyclic hendecapeptide that inhibits activation of fB and the AP. Structure-activity studies revealed that: 1) the cysteine-constrained structure of the peptide is essential for its activity; 2) Ile5, Arg6, Leu7, and Tyr8 contribute significantly to its inhibitory activity; and 3) retro-inverso modification of the peptide results in loss of its activity. Binding studies performed using surface plasmon resonance suggested that the peptide has two binding sites on fB, which are located on the Ba and Bb fragments. Studies on the mechanism of inhibition revealed that the peptide does not block the interaction of fB with the activated form of C3, thereby suggesting that the peptide inhibits fB activation primarily by inhibiting its cleavage by factor D. The peptide showed a weak effect on preformed C3 and C5 convertases. Like inhibition of fB cleavage, the peptide also inhibited C2 cleavage by activated C1s and activation of the classical as well as lectin pathways. Based on its inhibitory activities, we named the peptide Complin.

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Section: Discussionmentioning

confidence: 98%

Identification of Complin, a Novel Complement Inhibitor that Targets Complement Proteins Factor B and C2

Kadam

Sahu

2010

The Journal of Immunology

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“…This approach offers a direct way to assay for small molecules in the absence of structural, or practically any other information about the target protein. In addition, target validation can be conveniently done with the peptides before conducting large screening programs to search for the small-molecule compounds (Kay et al, 1998).…”

Section: Current Approaches To Increase the Chemical Diversity Of Biomentioning

confidence: 99%

Gelatinase-mediated migration and invasion of cancer cells

Björklund

Koivunen

2005

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

463

609

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“…rug development strategies for therapeutic peptides continue to be challenging despite advances in technologies such as pegylation and lipidation (1)(2)(3)(4). Although important biological processes are regulated by peptides, successful development of peptide drugs has been limited and transformation of a metabolically labile peptide into a drug remains challenging.…”

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confidence: 99%

Protein Engineering Strategies for Sustained Glucagon-Like Peptide-1 Receptor–Dependent Control of Glucose Homeostasis

Picha¹,

Cunningham²,

Drucker³

et al. 2008

Diabetes

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OBJECTIVE-We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform. It retains many activities of native GLP-1 yet has a significantly enhanced pharmacokinetic profile. Our goal was to develop a long-acting GLP-1 receptor agonist with sustained efficacy. RESEARCH DESIGN AND METHODS-In vitro and in vivo activity of CNTO736 was evaluated using a variety of rodent cell lines and diabetic animal models.RESULTS-Acute pharmacodynamic studies in diabetic rodents demonstrate that CNTO736 reduces fasting and postprandial glucose, decreases gastric emptying, and inhibits food intake in a GLP-1 receptor-specific manner. Reduction of food intake following CNTO736 dosing is coincident with detection of the molecule in the circumventricular organs of the brain and activation of c-fos in regions protected by the blood-brain barrier. Diabetic rodents dosed chronically with CNTO736 have lower fasting and postprandial glucose and reduced body weight. CONCLUSIONS-Takentogether, our data demonstrate that CNTO736 produces a spectrum of GLP-1 receptor-dependent actions while exhibiting significantly improved pharmacokinetics relative to the native GLP-1 peptide. Diabetes 57: [1926][1927][1928][1929][1930][1931][1932][1933][1934] 2008 D rug development strategies for therapeutic peptides continue to be challenging despite advances in technologies such as pegylation and lipidation (1-4). Although important biological processes are regulated by peptides, successful development of peptide drugs has been limited and transformation of a metabolically labile peptide into a drug remains challenging. In contrast, considerable advances have been made in the development of antibody therapeutics (5,6). A technology that could link the activity of a target peptide with the pharmacokinetic characteristics of an antibody would be a valuable addition to tools available for drug discovery. To address this need, we developed the MI-METIBODY platform as a novel technology for the display and delivery of bioactive peptides. Using protein design tools, we linked an antibody Fc domain to a bioactive glucagon-like peptide 1 (GLP-1) analog and engineered the construct for optimal biochemical and biophysical properties.GLP-1 is a 30 -amino acid peptide secreted from L-cells of the intestine following nutrient ingestion (7-10). GLP-1 is rapidly degraded in vivo with a half-life of Ͻ2 min and cleared via the kidney (11,12). When circulating glucose concentrations are elevated, GLP-1 increases insulin and decreases glucagon secretion from the pancreas and slows gastric emptying, thereby reducing glucose appearance in the circulation and enhancing glucose clearance from the circul...

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From peptides to drugs via phage display

Cited by 76 publications

References 92 publications

Identification of Complin, a Novel Complement Inhibitor that Targets Complement Proteins Factor B and C2

Identification of Complin, a Novel Complement Inhibitor that Targets Complement Proteins Factor B and C2

Gelatinase-mediated migration and invasion of cancer cells

Protein Engineering Strategies for Sustained Glucagon-Like Peptide-1 Receptor–Dependent Control of Glucose Homeostasis

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