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Lead Peptides (lead + peptide)
Selected AbstractsModeling an active conformation for linear peptides and design of a competitive inhibitor for HMG-CoA reductaseJOURNAL OF MOLECULAR RECOGNITION, Issue 4 2008Valeriy V. Pak Abstract This study presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized sequence. This approach was performed using the design of a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). In a previous design for constrained peptides, a head-to-tail cyclic structure of peptide was used as a model of linear analog in searches for lead peptides with a structure close to an active conformation. Analysis of the conformational space occupied by the peptides suggests that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. Using the space obtained by an analysis of the bioactive conformations of statins, eight cyclic peptides were selected for a peptide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion ("V" parameter) applied for constrained peptides. Three cyclic peptides (FGYVAE, FPYVAE, and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC50,=,0.4,µM) showed a 1200-fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC50,=,484,µM) from soybean. Experimental analysis of the modeled peptide structures confirms the appropriateness of the proposed approach for the modeling of active conformations of peptides. Copyright © 2008 John Wiley & Sons, Ltd. [source] Melanocortin ligands: 30 years of structure,activity relationship (SAR) studiesMEDICINAL RESEARCH REVIEWS, Issue 3 2004Jerry Ryan Holder Abstract The challenge of peptide and peptidomimetic research is the development of methods and techniques to improve the biological properties of native peptides and to convert peptide ligands into non-peptide compounds. Improved biological properties of peptides includes enhancement of stability, potency, and receptor selectivity, for both in vivo and in vitro applications. The design of a ligand with specific activity and desired biological properties is a complex task, and, to accomplish this objective, knowledge about putative interactions between a ligand and the corresponding receptor will be valuable. This includes interactions for both the binding and signal transduction processes. Structure,activity relationship (SAR) studies involve systematic modification of a lead peptide and are designed to provide insight into potential interactions involved in the formation of the ligand,receptor complex. It is desirable to have knowledge about both favorable and unfavorable processes that may occur in putative ligand,receptor interactions that result in either receptor stimulation or inhibition. Herein, we discuss various SAR studies that have involved melanocortin peptides over three decades and the information these studies have provided to the melanocortin field. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 3, 325,356, 2004 [source] Synthetic dsDNA-Binding Peptides Using Natural Compounds as ModelHELVETICA CHIMICA ACTA, Issue 6 2006Filip Borgions Abstract We have developed a series of short DNA-binding peptides containing newly synthesized, unnatural as well as natural amino acid building blocks. By a combinatorial-library approach, oligopeptides were developed with moderate dsDNA-binding affinities. Two strategies were used to further enhance the binding affinity of the lead peptides: Ac-Arg-Ual-Sar-Chi-Chi-Chi-Arg-NH2 and Ac-Arg-Cbg-Cha-Chi-Chi-Tal-Arg-NH2. Site-selective amino acid substitutions increased the binding affinities up to 2,×,10,5,M. Further enhancement of the binding affinities could be achieved by coupling of an acridine intercalating unit, using linker arms of different length and flexibility. With the introduction of a new lysine-based acridine unit, different types of oligopeptide,acridine conjugates were designed using known dsDNA-binding ligands as model compounds. The binding capacities of these new oligopeptide,acridine conjugates have been investigated by a fluorescent intercalator (ethidium bromide) displacement (FID) assay. With the synthesis of the dipeptide,acridine conjugates, binding affinities in the low micromolar range were obtained (6.4,×,10,6,M), which is similar to the binding strength of the well-known DNA binder Hoechst 33258. [source] Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG-CoA reductaseJOURNAL OF MOLECULAR RECOGNITION, Issue 4 2008Valeriy V. Pak Abstract This study presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized sequence. This approach was performed using the design of a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). In a previous design for constrained peptides, a head-to-tail cyclic structure of peptide was used as a model of linear analog in searches for lead peptides with a structure close to an active conformation. Analysis of the conformational space occupied by the peptides suggests that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. Using the space obtained by an analysis of the bioactive conformations of statins, eight cyclic peptides were selected for a peptide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion ("V" parameter) applied for constrained peptides. Three cyclic peptides (FGYVAE, FPYVAE, and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC50,=,0.4,µM) showed a 1200-fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC50,=,484,µM) from soybean. Experimental analysis of the modeled peptide structures confirms the appropriateness of the proposed approach for the modeling of active conformations of peptides. Copyright © 2008 John Wiley & Sons, Ltd. [source] Solution structure of nociceptin peptidesJOURNAL OF PEPTIDE SCIENCE, Issue 9 2002Pietro Amodeo Abstract Peptides embedded in the sequence of pre-pro-nociceptin, i.e. nociceptin, nocistatin and orphanin FQ2, have shed light on the complexity of the mechanisms involving the peptide hormones related to pain and have opened up new perspectives for the clinical treatment of pain. The design of new ligands with high selectivity and bioavailability, in particular for ORL1, is important both for the elucidation and control of the physiological role of the receptor and for their therapeutic importance. The failure to obtain agonists and antagonists when using, for nociceptin, the same substitutions that are successful for opioids, and the conformational flexibility of them all, justify systematic efforts to study the solution conformation under conditions as close as possible to their natural environment. Structural studies of linear peptides in solution are hampered by their high flexibility. A direct structural study of the complex between a peptide and its receptor would overcome this difficulty, but such a study is not easy since opioid receptors are membrane proteins. Thus, conformational studies of lead peptides in solution are still important for drug design. This review deals with conformational studies of natural pre-nociceptin peptides in several solvents that mimic in part the different environments in which the peptides exert their action. None of the structural investigations yielded a completely reliable bioactive conformation, but the global conformation of the peptides in biomimetic environments can shed light on their interaction with receptors. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd. [source] | ||||||||||