Discovering and improving novel peptide therapeutics
Cyclogenix Limited, Crombie Lodge, Aberdeen Science & Technology Park, Aberdeen, UK. Current Opinion in Pharmacology
(Impact Factor: 4.6).
08/2008; 8(5):616-9. DOI: 10.1016/j.coph.2008.06.002
Peptides have a number of advantages over small molecules in terms of specificity and affinity for targets, and over antibodies in terms of size. However, sensitivity to serum and tissue proteases coupled with short serum half-life has resulted in few recombinant library derived peptides, making the transition from lead to drug on the market. Recently, a series of technologies have been developed to address both these issues: selection methodologies addressing protease resistance have been developed that when combined with methods such as pegylation antibody Fc attachment and binding to serum albumin look likely to finally turn therapeutic peptides into a widely accepted drug class.
Available from: Gurpreet Singh
- "Bioactive proteins from Solanaceae as quorum sensing inhibitors against virulence in Pseudomonas aeruginosa . Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.02.019 metabolites or small organic molecules that are employed in QSI studies exhibited a range of properties , they are known to exert metabolic stress in host much greater than primary metabolites or proteins . Further, concerns with toxicity remain a blockade for their commercial or therapeutic use, as in brominated furanones which are among the first recognized small-molecule inhibitors of QS . "
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ABSTRACT: Cell-to-cell communication or quorum sensing (QS) is a generic event in bacteria that is used to coordinate gene expression among local populations. The phenomenon of QS depends on the fact that presence of sufficient bacteria ascertains a threshold level of autoinducer concentration that allows bacteria to sense a critical cell mass and to activate or repress target genes. Thus, QS has been an attractive target for the development of anti-infective strategies that are not based on the use of antibiotics. Several anti-QS approaches have been demonstrated including natural products from plant-based secondary metabolites. However, the role of plant bioactive proteins as an anti-QS peptide is yet to be deciphered. Against a backdrop of ever-increasing antibiotic resistant pathogens, there is a strong need for development of alternative therapeutic strategies. Thus, our hypothesis is that bioactive proteins from the plant family Solanaceae are quorum quenching molecules that can be exploited to develop a therapeutic strategy against virulence. We presume that bioactive proteins will inactivate or inhibit or degrade QS signals from bacteria to prevent cell-to-cell communication and thus inhibit development of virulence in Pseudomonas aeruginosa. Further, the use of proteins as quorum quenchers will delay the bacteria to develop resistance against these quenching molecules.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Medical Hypotheses 03/2015; 20(6). DOI:10.1016/j.mehy.2015.02.019 · 1.07 Impact Factor
Available from: Gajendra Pal Singh Raghava
- "The field of therapeutic peptides is growing very rapidly due to substantial technological progress (1,17). Literature on therapeutic peptides is rapidly adding (18), and therefore in the past few years only, many comprehensive databases of various therapeutic peptides including antimicrobial peptides (5,6), cell-penetrating peptides (19), tumor-homing peptides (20) and quorum-sensing peptides (21) have been developed. In addition, an interesting and useful resource of blood–brain barrier peptides—Brainpeps—(22) has also been developed recently. "
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ABSTRACT: Hemolytik (http://crdd.osdd.net/raghava/hemolytik/) is a manually curated database of experimentally determined hemolytic and non-hemolytic peptides. Data were compiled from a large number of published research articles and various databases like Antimicrobial Peptide Database, Collection of Anti-microbial Peptides, Dragon Antimicrobial Peptide Database and Swiss-Prot. The current release of Hemolytik database contains ∼3000 entries that include ∼2000 unique peptides whose hemolytic activities were evaluated on erythrocytes isolated from as many as 17 different sources. Each entry in Hemolytik provides comprehensive information about a peptide, like its name, sequence, origin, reported function, property such as chirality, types (linear and cyclic), end modifications as well as details pertaining to its hemolytic activity. In addition, tertiary structure of each peptide has been predicted, and secondary structure states have been assigned. To facilitate the scientific community, a user-friendly interface has been developed with various tools for data searching and analysis. We hope, Hemolytik will be useful for researchers working in the field of designing therapeutic peptides.
Nucleic Acids Research 10/2013; 42(Database issue). DOI:10.1093/nar/gkt1008 · 9.11 Impact Factor
Available from: Henry Daniell
- "Despite these advantages, therapeutic peptides have several limitations. They are highly prone to proteolytic degradation during storage or when used for oral administration (McGregor, 2008) and require parenteral administration. In addition, these peptides need cold storage due to short shelf life after purification or chemical synthesis. "
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ABSTRACT: Glucagon-like peptide (GLP-1) increases insulin secretion but is rapidly degraded (half-life: 2 min in circulation). GLP-1 analogue, exenatide (Byetta) has a longer half-life (3.3-4 h) with potent insulinotropic effects but requires cold storage, daily abdominal injections with short shelf life. Because patients with diabetes take >60 000 injections in their life time, alternative delivery methods are highly desired. Exenatide is ideal for oral delivery because insulinotropism is glucose dependent, with reduced risk of hypoglycaemia even at higher doses. Therefore, exendin-4 (EX4) was expressed as a cholera toxin B subunit (CTB)-fusion protein in tobacco chloroplasts to facilitate bioencapsulation within plant cells and transmucosal delivery in the gut via GM1 receptors present in the intestinal epithelium. The transgene integration was confirmed by PCR and Southern blot analysis. Expression level of CTB-EX4 reached up to 14.3% of total leaf protein (TLP). Lyophilization of leaf material increased therapeutic protein concentration by 12- to 24-fold, extended their shelf life up to 15 months when stored at room temperature and eliminated microbes present in fresh leaves. The pentameric structure, disulphide bonds and functionality of CTB-EX4 were well preserved in lyophilized materials. Chloroplast-derived CTB-EX4 showed increased insulin secretion similar to the commercial EX4 in beta-TC6, a mouse pancreatic cell line. Even when 5000-fold excess dose of CTB-EX4 was orally delivered, it stimulated insulin secretion similar to the intraperitoneal injection of commercial EX4 but did not cause hypoglycaemia in mice. Oral delivery of the bioencapsulated EX4 should eliminate injections, increase patient compliance/convenience and significantly lower their cost.
Plant Biotechnology Journal 10/2012; 11(1). DOI:10.1111/pbi.12008 · 5.75 Impact Factor
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