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Journal of Chemical Information and... Feb 2019Peptide-binding domains have been successfully targeted in therapeutic applications. However, many peptide-binding proteins (PBPs) remain uncharacterized. Computational...
Peptide-binding domains have been successfully targeted in therapeutic applications. However, many peptide-binding proteins (PBPs) remain uncharacterized. Computational prediction of peptide-domain interfaces is challenging due to short lengths, lack of well-defined structures, and limited conservation of peptide motifs. Here we present SPOT-peptide, a template-based protocol for the simultaneous prediction of peptide-binding domains and peptide binding sites independent of specific peptide composition. SPOT-peptide leverages the dogmatic relationship between protein structure and function to predict peptide-binding characteristics for an unknown target based on remote structural homologues. In a leave-homologue out benchmark evaluation, PBPs are discriminated with a Matthews correlation coefficient (MCC) of 0.420 and the correct binding sites are identified in 80% of the predicted PBPs. Furthermore, replacing the holo target structures with equivalent structures in the apo conformation only marginally diminished PBP recovery. The method is available as a web server at http://sparks-lab.org/tom/SPOT-peptide .
Topics: Binding Sites; Models, Molecular; Peptides; Protein Binding; Protein Domains; Proteins
PubMed: 30698427
DOI: 10.1021/acs.jcim.8b00777 -
Journal of Controlled Release :... Jun 2017Peptide therapeutics is currently one of the fastest growing markets worldwide and consequently convenient ways of administration for these drugs are highly on demand.... (Review)
Review
Peptide therapeutics is currently one of the fastest growing markets worldwide and consequently convenient ways of administration for these drugs are highly on demand. In particular, oral dosage forms would be preferred. A relative large molecular weight and high hydrophilicity, however, result in comparatively very low oral bioavailability being in most cases below 1%. Lipid based formulations (LBF), in particular self-emulsifying drug delivery systems (SEDDS) and solid lipid nanoparticles (SLN) as well as liposomes are among the most promising tools for oral peptide delivery. Key to success in orally delivering peptides via LBF seems to be a sufficiently high lipophilic character of those therapeutic agents. Hence, different non-covalent and covalent peptide lipidization methods from drug delivery point of view are presented. On the one hand, among non-covalent lipidization methods hydrophobic ion pairing seems to be a promising way to sufficiently increase peptide lipophilicity providing high drug payloads in the lipid phase, a protective effect against presystemic metabolism via thiol-disulphide exchange reactions and proteolysis as well as an improved intestinal membrane permeability. On the other hand, covalent methods like conjugating fatty acids via amidation, esterification, reversible aqueous lipidization (REAL) and cyclization also show potential. The present review therefore describes those lipidization methods in detail and critically evaluates their contribution in successfully overcoming the oral barriers.
Topics: Administration, Oral; Animals; Drug Delivery Systems; Humans; Intestinal Absorption; Lipids; Peptides; Proteolysis; Vaccines
PubMed: 28457894
DOI: 10.1016/j.jconrel.2017.04.038 -
Bioorganic & Medicinal Chemistry Jun 2018The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral... (Review)
Review
The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral availability of most peptides is a certain limitation. Whereas metabolic instability may be often overcome by development of small cyclic peptides containing d-amino acids, the very low oral availability of most peptides is a serious limitation for some medicinal applications. The situation is complicated because a twofold optimization - biological activity and oral availability - is required to overcome this problem. Moreover, most simple "rules" for achieving oral availability are not general and are applicable only to limited cases. Many structural modifications for increasing biological activities and metabolic stabilities of cyclic peptides have been described, of which N-alkylation is probably the most common. This mini-review focuses on the effects of N-methylation of cyclic peptides in strategies to optimize bioavailabilities.
Topics: Animals; Biological Availability; Cell Membrane Permeability; Drug Discovery; Humans; Methylation; Peptides, Cyclic; Peptidomimetics
PubMed: 28886995
DOI: 10.1016/j.bmc.2017.08.031 -
Peptides Apr 2016Peptide YY 3-36-amide (PYY3-36) is a peptide hormone, which is known to decrease appetite and food-intake by activation of the Y2 receptor. The current studies were...
Peptide YY 3-36-amide (PYY3-36) is a peptide hormone, which is known to decrease appetite and food-intake by activation of the Y2 receptor. The current studies were designed to identify the metabolites of PYY3-36 in mini-pig and rhesus monkey. Plasma samples were analyzed by high resolution LC-MS (and MS/MS) in order to unambiguously identify the metabolites of PYY3-36. In summary, the metabolism of PYY3-36 was similar in mini-pig and rhesus monkey. Several metabolites were identified and PYY3-34 was identified at the highest levels in plasma. In addition, mini-pigs were also dosed with PYY1-36-amide, PYY3-35, PYY3-34 and [N-methyl 34Q]-PYY3-36-amide in order to investigate the mechanisms by which PYY was metabolized. PYY3-35 was rapidly converted to PYY3-34 whereas dosing of PYY3-34 to mini-pigs only showed circulating degradation products at low levels, i.e., PYY3-34 was metabolically more stable than PYY3-36 and PYY3-35. [N-methyl 34Q]-PYY3-36-amide was hypothesized to be stable toward cleavage between 34Q and 35R and after i.v. administration to mini-pigs, one major cleavage product was identified as [N-methyl 34Q]-PYY3-35. Overall, this showed that cleavage between 35R and 36Y was possible as well as between 34Q and 35R (as shown for PYY3-35), which indicated that metabolism of PYY3-36 to PYY3-34 may be a two-step process. PYY1-36 was also dosed to mini-pigs, which showed that PYY1-36 was metabolized in the C-terminal as PYY3-36. The overall degradation pattern of PYY1-36 was more complex due to the simultaneous enzymatic degradation in the N-terminal to form PYY2-34/36 and PYY3-34/36. In vitro incubations with heparin stabilized plasma showed that PYY3-36 was degraded with a half-life of 175 min, whereas incubations with PYY3-35 (half-life of 6 min) showed a rapid formation of PYY3-34. In conclusion, the present studies showed that PYY3-36 underwent enzymatic degradation in the C-terminal part and that the major circulating metabolite was PYY3-34. Furthermore, it may be a sequential two-step process leading to the formation of PYY3-35 and subsequently the metabolically more stable PYY3-34.
Topics: Animals; Appetite; Biotransformation; Chromatography, Liquid; Eating; Female; Half-Life; Macaca mulatta; Male; Peptide Fragments; Peptide YY; Proteolysis; Receptors, Neuropeptide Y; Swine; Swine, Miniature; Tandem Mass Spectrometry
PubMed: 26774588
DOI: 10.1016/j.peptides.2016.01.010 -
European Journal of Medicinal Chemistry Apr 2015Peptide macrocycles represent a chemical space where the best of biological tools can synergize with the best of chemical approaches in the quest for leads against... (Review)
Review
Peptide macrocycles represent a chemical space where the best of biological tools can synergize with the best of chemical approaches in the quest for leads against undruggable targets. Peptide macrocycles offer some key advantages in both lead discovery and lead optimization phases of drug discovery when compared to natural product and synthetic macrocycles. In addition, they are uniquely positioned to capitalize on the therapeutic potential of peptides because cyclization can help drive selectivity, potency and overcome the common limitations of metabolic instability of peptides.
Topics: Cyclization; Drug Discovery; Humans; Macrocyclic Compounds; Peptides; Protein Stability
PubMed: 25109255
DOI: 10.1016/j.ejmech.2014.07.083 -
Peptides Dec 2021The continued use of antibiotics has been accompanied by the rapid emergence and spread of antibiotic-resistant strains of bacteria. Antimicrobial peptides (AMPs), also... (Review)
Review
The continued use of antibiotics has been accompanied by the rapid emergence and spread of antibiotic-resistant strains of bacteria. Antimicrobial peptides (AMPs), also known as host defense peptides, show multiple features as an ideal antimicrobial agent, including potent, rapid, and broad-spectrum antimicrobial activity, low promotion of antimicrobial resistance, potent anti-biofilm activity, and lethality against metabolically inactive microorganisms. However, several crucial drawbacks constrain the use of AMPs as clinical drugs, e.g., liability in vivo, toxicity when used systemically, and high production costs. Based on recent findings and our own experiences, here we summarize some chemical modifications and key design strategies to increase the therapeutic potential of AMPs, including 1) enhancing antimicrobial activities, 2) improving in vivo effectiveness, and 3) reduction in toxicity, which may facilitate the design and optimization of AMPs for the development of drug candidates. We also discuss the present challenges in the optimization of AMPs and future concerns about the resistance and cross-resistance to AMPs in the development of AMPs as therapeutic drugs.
Topics: Antimicrobial Peptides; Cyclization; Humans; Microbial Sensitivity Tests; Nanoparticles; Protein Stability; Structure-Activity Relationship
PubMed: 34600037
DOI: 10.1016/j.peptides.2021.170666 -
Methods in Molecular Biology (Clifton,... 2020The application of designer peptides in medicinal chemistry, chemical biology, and materials science has generated new interest in synthetic methods for the structural...
The application of designer peptides in medicinal chemistry, chemical biology, and materials science has generated new interest in synthetic methods for the structural modification of amino acids. Strategies which facilitate the direct diversification of proteinogenic functional groups within unprotected peptide substrates are particularly attractive as they leverage modern solution- and solid-phase protocols-tools which are now both robust and routine-for the synthesis of native peptides. Accordingly, a recent approach to the decarboxylative functionalization of peptidic carboxylic acids, including aspartic/glutamic acid residues and α-carboxylic acids, has proven to be a promising new strategy for peptide modification. This synthetic method merges conventional strategies for the activation of carboxylic acids with transition metal-catalyzed cross-coupling chemistry to forge new C-C bonds for the late-stage introduction of valuable synthetic handles. This chapter details a step-by-step protocol for the activation and nickel-catalyzed decarboxylative alkylation of a simple peptide substrate to highlight the broad utility of this strategy for the synthesis of designer peptides.
Topics: Amino Acids; Carboxylic Acids; Decarboxylation; Ligands; Metals; Nickel; Oxidative Coupling; Peptides; Solid-Phase Synthesis Techniques
PubMed: 31879933
DOI: 10.1007/978-1-0716-0227-0_19 -
Journal of Molecular Endocrinology May 2016Proopiomelanocortin (POMC) is a complex precursor that comprises several peptidic hormones, including melanocyte-stimulating hormones (MSHs), adrenocorticotropic hormone... (Review)
Review
Proopiomelanocortin (POMC) is a complex precursor that comprises several peptidic hormones, including melanocyte-stimulating hormones (MSHs), adrenocorticotropic hormone (ACTH), and β-endorphin. POMC belongs to the opioid/orphanin gene family, whose precursors include either opioid (YGGF) or the orphanin/nociceptin core sequences (FGGF). This gene family diversified during early tetraploidizations of the vertebrate genome to generate four different precursors: proenkephalin (PENK), prodynorphin (PDYN), and nociceptin/proorphanin (PNOC) as well as POMC, although both PNOC and POMC seem to have arisen due to a local duplication event. POMC underwent complex evolutionary processes, including internal tandem duplications and putative coevolutionary events. Controversial and conflicting hypotheses have emerged concerning the sequenced genomes. In this article, we summarize the different evolutionary hypotheses proposed for POMC evolution.
Topics: Animals; Biological Evolution; Evolution, Molecular; Gene Expression Regulation; Humans; Multigene Family; Organ Specificity; Peptide Hormones; Pro-Opiomelanocortin; Protein Processing, Post-Translational; Proteolysis
PubMed: 26671895
DOI: 10.1530/JME-15-0288 -
Peptides May 2015Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. In this process, a single transcript... (Review)
Review
Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. In this process, a single transcript yields different mature RNAs leading to the production of protein isoforms with diverse or even antagonistic functions. During splicing events, errors can be caused either by mutations present in the genome or by defects or imbalances in regulatory protein factors. In any case, defects in alternative splicing have been related to several genetic diseases including muscular dystrophy, Alzheimer's disease and cancer from almost every origin. One of the most effective approaches to redirect alternative splicing events has been to attach cell-penetrating peptides to oligonucleotides that can modulate a single splicing event and restore correct gene expression. Here, we summarize how natural existing and bioengineered peptides have been applied over the last few years to regulate alternative splicing and genetic expression. Under different genetic and cellular backgrounds, peptides have been shown to function as potent vehicles for splice correction, and their therapeutic benefits have reached clinical trials and patenting stages, emphasizing the use of regulatory peptides as an exciting therapeutic tool for the treatment of different genetic diseases.
Topics: Alternative Splicing; Amino Acid Sequence; Animals; Base Sequence; Cell-Penetrating Peptides; Genetic Diseases, Inborn; Humans; Molecular Sequence Data; Peptide Nucleic Acids; Protein Isoforms; Transfection
PubMed: 25748022
DOI: 10.1016/j.peptides.2015.02.006 -
International Journal of Pharmaceutics Jul 2021The physical and chemical stability of therapeutic peptides presents challenges in developing robust formulations. The stability of the formulation affects product...
The physical and chemical stability of therapeutic peptides presents challenges in developing robust formulations. The stability of the formulation affects product safety, efficacy and quality. Therefore, an understanding of the effects of formulation variables on the peptide's conformational structure and on its possible physical and chemical degradation is vital. To this end, computational and experimental analysis were employed to investigate the impact of formulation, peptide folding and product handling on oxidation, fibrillar aggregation and gelation of teriparatide. Teriparatide was used as a model drug due to the correlation of its conformation in solution with its pharmacological activity. Fibrillar aggregation and gelation were monitored using four orthogonal techniques. An innovative, automated platform coupled with ion mobility mass spectrometry was used for profiling chemical degradants. Increases in teriparatide concentration, pH, and ionic strength were found to increase the rate of fibrillar aggregation and gelation. Conversely, an increase in peptide folding and stabilization of the folded structures was found to decrease the rate of fibrillar aggregation and gelation. Moreover, the rate of oxidation was found to be inversely related to its solution concentration and extent of peptide folding. The present study provides an insight into formulation strategies designed to reduce the potential risk of physical and chemical degradation of peptides with a defined conformation.
Topics: Molecular Conformation; Osmolar Concentration; Oxidation-Reduction; Peptides
PubMed: 33961953
DOI: 10.1016/j.ijpharm.2021.120677