686 research outputs found
Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday
No full textAdvances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery is a book dedicated to Prof. Victor J. Hruby on the occasion of his 80th birthday. This book includes twenty contributions from authors representing diverse multidisciplinary fields of scientific expertise, and is focused on the extraordinary potential of peptides and peptidomimetics as a surging therapeutic modality and as tools for basic research and technology development
Rational Approach to the Design of Bioactive Peptidomimetics: Recent Developments in Opioid Agonist Peptides
No full textPharmacological management of severe and chronic pain remains a difficult achievement with currently available analgesic drugs. The design and development of potent opioid analogs with reduced tolerance, dependence, respiratory depression, and other unwanted side effects, could be of great value in the clinical treatment of chronic pain. The hierarchical approach to peptidomimetic design has dramatically advanced over the past three decades; a significant target in research since the discovery of multiple opioid receptors has been to develop highly potent and selective opioid receptor peptidomimetics that overcome the problems related to scarce bioavailability, enzymatic degradation, and low safety profile of natural peptides.
Peptide drug design is a high multidisciplinary area that often relies on the state-of-the-art of organic chemistry, pharmacology, and biochemistry, computational methods and biophysical methods for determining the structural, conformational, topographical, and dynamic properties of designed ligands. With the aim to explore the recent advancements in opioids research, in this chapter, particular attention has been paid on the structural modifications of natural opioid peptides to obtain potent, selective, and stable opioid agonists. In addition, we focused our attention on μ/δ mixed agonists and novel approaches based on multitarget ligands, as discussed in section “Future Perspectives and Conclusions.
Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors
No full textWe
report the development of macrocyclic melanocortin derivatives
of MT-II and SHU-9119, achieved by modifying the cycle dimension and
incorporating constrained amino acids in ring-closing. This study
culminated in the discovery of novel agonists/antagonists with an
unprecedented activity profile by adding pieces to the puzzle of the
melanocortin receptor selectivity. Finally, the resulting 19- and
20-membered rings represent a suitable frame for the design of further
therapeutic ligands as selective modulators of the melanocortin system
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Structure-activity studies of delta-selective opioid analogues
No full textThe two structurally different peptides DPDPE and Dermenkephalin show a similar remarkably high affinity and selectivity for the delta opioid receptor subtype. An effort has been made to gain some insight into the factors responsible for the recognition ability of these two molecules by synthesizing some DPDPE-Dermenkephalin peptide hybrids and some conformationally restricted Dermenkephalin analogues. The results of the binding and the in-vitro bioassays have been compared with those of the parent peptides. A general decrease in receptor affinity has been observed in the peptide hybrids while the dermenkephalin analogues have shown a wider range of affinities and selectivities. The above findings contribute to the understanding of the structural requirements of the delta receptor, provide information about the sensitivity of Dermenkephalin to enzymatic degradation, and indicate directions for future research
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Design and synthesis of conformationally and topographically constrained amino acids as peptidomimetics
No full textA major goal of peptide research has been to elucidate or understand the relationships between a peptide's three-dimensional structure and its biological activity. De Novo design of peptide mimetics requires assembling all components necessary for molecular recognition and transduction, which needs the proper choice of a template that can place the key side chain residues in 3D space. Two widely used methods are novel β-substituted amino acids and conformationally constrained secondary structure mimetics. In this thesis, we report our efforts to fulfill the aforementioned criteria in synthesizing β-isopropyl aromatic amino acids and constrained reverse turn dipeptide mimetics. Through asymmetric Michael addition reaction, highly topographically constrained β-isopropyl aromatic amino acids have been synthesized. In order to develop a general approach to synthesize these novel amino acids, we re-examined the reaction conditions for Evans' diastereoselective 1,4-addition, and found conditions which gave excellent diastereoselectivities and good chemical yields. A concise and straightforward five-step synthesis of [5.5]-bicyclic reverse turn dipeptide mimetic scaffolds with side chain functionality at the i+1 and i+2 positions has been developed. In the bicyclic structure, two dihedral angles (ψ₂ and φ₃) are greatly restricted. Further development of this synthesis will enable us to prepare various types of reverse turns with different backbone geometry and side chain topography. Enantiomerically pure (S)-trans-cinnamylglycine and (S)-α-trans-cinnamyl-α-alanine have been prepared via reaction of chiral Ni (II)-complexes of glycine and alanine respectively, with cinnamyl halides. Inexpensive and readily available reagents and solvents are used, including a recyclable chiral ligand. The simplicity of the experimental procedures and high stereochemical outcome make this method synthetically attractive for preparing the target amino acids on multi-gram scales. Further studies by incorporating these mimetics into potent peptide analogues will greatly help us to understand the bioactive conformation of the parent peptides
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The design and synthesis of novel beta-substituted amino acids, bicyclic dipeptide mimetics, and their incorporation into cholecystokinin/opioidchimeric peptides
No full textPeptide ligands and protein receptors play critical roles in the regulation of nearly every biological system. However, peptides are characteristically highly flexible and thus identifying the basic conformational elements necessary for recognition between a peptide ligand and it's receptor at the molecular level remains a formidable task. Great emphasis in peptide research has thus focused on the determination of the receptor-bound conformation adopted by bioactive peptides by synthesizing constrained analogues of the peptides. Knowledge of the three dimensional interaction between a peptide ligand and a receptor could be invaluable in understanding bioactivity and in the design of therapeutics. To determine the bioactive conformation of our novel chimeric peptides for the opioid and cholecystokinin receptors, constrained analogues were designed to limit the conformations that the peptides would adopt. In this regard, [5,5]- and [6,5]-bicyclic dipeptide mimetics were designed and synthesized to constrain a dipeptide unit and by extension limit the flexibility of the peptide. The bicyclic dipeptide mimetics were synthesized from precursors obtained by the beta-alkylation of aspartic acid and from the Kazmaier-Claisen rearrangement reaction. A protocol for the alkylkation of aspartic acid with allyl bromide, benzyl bromide, and benzyl disulfide was developed. The bicyclic dipeptide mimetics were then introduced into the peptides whose biological activity was evaluated at both the opioid and cholecystokinin receptors. The peptides showed good binding and functional activities at the CCK receptors, but low activities at the opioid receptors
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Synthesis of Novel Biologically Active Peptide Analogues that are Agonists at Opioid Receptors and Antagonists at Cholecystokinin Receptors
No full textWe know that many disease states lead to changes in expressed proteins. Therefore, drug design and discovery based on normal states and single targets often is inadequate. The "system changes" that occurs must be considered in any treatment for the disease, clearly evident in neuropathic pain where opioids can actually heighten pain. To effectively treat diseases involving "systems changes" a new paradigm was recently introduced. In this new approach single peptide molecules are designed to interact with multiple receptor targets. For the treatment of pain, a series of linear and cyclic peptides were designed based on the overlapping pharmacophores of opioid and CCK ligands. The opioid/CCK analogues were synthesized and evaluated for their biological activities. Several analogues were found to simultaneously interact with opioid receptors as agonists and CCK receptors as antagonists. This study further modifies the RSA analogues to improve on the bioassays of the previous peptides
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DESIGN AND SYNTHESIS OF STRUCTURAL, STEREOISOMERIC AND CONFORMATIONALLY RESTRICTED ANALOGUES OF ALPHA-MELANOTROPIN: COMPARATIVE BIOLOGICAL PROPERTIES ON MELANOPHORES AND MELANOMA CELLS
No full textSeveral chemically-modified analogues of α-melanotropin (α-MSH, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂) were prepared by solid-phase peptide synthesis, including [Nle⁴]-α-MSH, Ac-[Nle⁴]-α-MSH₄₋₁₃-NH₂, Ac-[Nle⁴]-α-MSH₁₋₆-NH₂, Ac-α-MSH₇₋₁₀-NH₂, Ac-α-MSH₁₁₋₁₃-NH₂, Ac-[Nle⁴]-α-MSH(,4-10)-NH₂, Ac-[Nle⁴, D-Phe⁷]-α-MSH₄₋₁₀-NH₂, [Nle⁴, D-Phe⁷]-α-MSH, Ac-α-MSH₄₋₁₀-NH₂, Ac-[Tyr⁴]-α-MSH₄₋₁₀-NH₂ and [half-Cys⁴, half-Cys¹⁰]-α-MSH. The synthetic strategy involved: (1) p-methylbenzhydrylamine resin as a solid support, (2) N,N'-dicyclohexylcarbodiimide as a coupling reagent, (3) acetylation of the N-terminus and HF cleavage and deprotection (except for Nⁱ-For-Trp) of the fully assembled peptide-resin and (4) alkaline hydrolysis to deformylate Nⁱ-For-Trp. In the preparation of [half-Cys⁴, half-Cys¹⁰]-α-MSH, oxidative-cyclization provided formation of an intramolecular disulfide bridge. A comparative biological analysis in vitro of these above structural, stereoisomeric and conformationally-restricted analogues of α-MSH on several different vertebrate pigment cell systems provided the following results: (1) The [Nle⁴, D-Phe⁷]-α-MSH effected high melanotropic potency (> 60 times relative to α-MSH), ultralong biological activity and unprecedented metabolic stability. (2) Utilizing [Nle⁴, D-Phe⁷]-α-MSH as a molecular probe, two melanotropic receptor types were demonstrated which were mechanistically different in terms of calcium dependency and apparent hormone-receptor complex reversibility. (3) The Ac-[Nle⁴, D-Phe⁷]-α-MSH₄₋₁₀-NH₂ was a highly potent active site (Met-Glu-His-Phe-Arg-Trp-Gly) analogue of α-MSH (ranging from 0.2- to 10-times relative to α-MSH) without the ultralong melanotropic activity possessed by the parent stereostructural tridecapeptide. (4) The [half-Cys4, half-Cys10]-α-MSH exhibited superpotency on frog (Rana pipiens) melanophores (≥ 10,000 times relative to α-MSH), and provided experimental evidence that a pseudocyclic conformation of the native hormone containing a β-turn structural requirement at His-Phe-Arg-Trp might be related to its biological activity at the pigment cell receptor. The [Nle⁴, D-Phe⁷]-α-MSH may be suitable for use as a radio-labeled tracer or drug-delivery agent for the localization or treatment of human melanoma in vivo.This item was digitized from a paper original and/or a microfilm copy. If you need
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Design and synthesis of topographically constrained amino acids, and bioactive peptides for studies of ligand-receptor interaction, and for de novo design of delta-opioid selective non-peptide mimetics as potential therapeutics
No full textTopographical constraint is the most powerful approach for the design of bioactive peptides to explore the bioactive conformation of crucial side-chain pharmacophores of amino acid residues in peptide-receptor recognition and signal transduction. Novel topographically constrained amino acids β-isopropylphenylalanine and 2',6'-dimethyl-2,3-methanophenylalanine have been designed and synthesized. Incorporation of the four optically pure β-isopropylphenylalanine stereoisomers into deltorphin I produced four peptide analogues of [β-iPrPhe]Deltorphin I with differentiated bioactivities. The most potent and selective analogue, [(2S,3R)-β-iPrPhe]Deltorphin I showed an IC₅₀ nM binding affinity, and a 29000 fold selectivity for the δ-opioid receptor over the μ opioid receptor. Combined molecular modeling and NMR studies indicated that the (2S,3R)-β-iPrPhe³ residue in the analogue favors the trans rotamer, and can induce the linear peptide to form a low-energy folded conformation which was proposed as the bioactive conformation for the δ-opioid receptor. Coupling four optically pure, conformationally constrained β-methyl-2',6'-dimethyltyrosine (TMT) with L-Tic formed four dipeptide analogues of TMT-L-Tic. The most potent and selective analogue, (2S,3R)-TMT-L-Tic showed 9 nM binding affinity and 4000 fold selectivity to the δ vs μ opioid receptor. The lowest-energy conformation of (2S,3R)-TMT-L-Tic was suggested to be the bioactive one in which TMT side chain is trans and Tic side chain is in a gauche (+) conformation. Bicyclic oxytocin antagonist [dPen¹, cyclo(Glu⁴ Lys⁸)]OT (BC-OT) (pA₂ = 8.10) is an excellent template to examine further topographical ideas. Substitution of Tyr² with the topographically constrained para-methoxy-β-methyl-2',6'-dimethyltyrosine (p-MeOTMT) amino acids produced two very potent antagonists [(2S,3S)-p-MeOTMT²]BC-OT (pA₂ = 8.26) and [(2R,3R)-p-MeOTMT²]BC-OT(pA₂ = 7.80), and two inactive analogues [(2S,3R)-p-MeOTMT²]BC-OT and [(2R,3S)-p-MeOTMT²]BC-OT. These interesting results can be attributed to the biased side-chain conformation, gauche(+) and gauche(-) in (2S,3S)-p-MeOTMT and (2R,3R)-p-MeOTMT respectively, and trans in both (2S,3R)-p-MeOTMT and (2R,3S)-p-MeOTMT residues. Rational design of non-peptide mimetics from peptide leads is still elusive. Based on the δ-opioid selective lead [(2S,3R)-TMT¹]DPDPE and SAR of δ-opioid selective ligands, the first generation of non-peptide mimetics have been designed and synthesized. The new lead SL-3111 showed binding affinity IC₅₀ = 8 nM, and over 2000 fold selectivity for the δ-opioid receptor over the μ receptor.This item was digitized from a paper original and/or a microfilm copy. If you need higher-resolution images for any content in this item, please contact us at [email protected] file replaced with corrected file October 2023
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Development of new conformationally and topographically constrained p60(c-src) PTK inhibitors. Solution and solid-phase approaches for the synthesis of delta-opioid receptor peptidomimetic ligands
No full textBased on the efficient substrate for p60ᶜ⁻ˢʳᶜ protein tyrosine kinase (PTK) YIYGSFK (1) (K(m) = 55 μM) obtained by combinatorial methods, we have designed and synthesized a series of conformationally and topographically constrained substrate-based peptide inhibitors for this enzyme. The inhibitors showed IC₅₀ values in low micromolar range (0.1-3 μM). A "rotamer scan" was performed by introducing four stereoisomers of β-Me(2')Nal in the postulated interaction site of peptide inhibitor (23) Y-c[D-Pen-(2')Nal-GSFC]KR-NH₂ (IC₅₀ = 1.6 μM). We found that the χ¹ space constraints imposed by the specialized amino acids, introduced at position 3 of peptide 23, were not as important as the configuration of the Cᵅ of that residue to recognize the active site of Src and Lck PTK, as reflected on the observed selectivity ratios. Cocrystallization studies between Lck and two of our inhibitors are in progress, in a collaboration with Dr. X. Zhu (Kinetix, Pharmaceuticals, Inc.). The results obtained may serve as the basis for the design of Lck and/or Src inhibitors, either peptide or nonpeptide. SL-3111 is a high affinity (IC₅₀ = 8.4 nM) and selective (μ/δ = 2020) δ-opioid receptor peptidomimetic ligand developed in Dr. Hruby's laboratory, as the result of extensive structure-activity relationship (SAR) studies based on peptide leads. However, bioassays (GPI and MVD) and in-vivo antinociception studies on the racemic mixture and both enantiomers of this compound, have shown particular problems such as low potency and toxicity. We have shown the importance of the piperazine ring in this molecule for binding toward the δ-opioid receptor. Thus, maintaining such scaffold we have studied a series of solution and solid-phase approaches toward the synthesis of SL-3111 analogues, which explore wider functional diversity at this heterocyclic ring. Compounds 64-67 were synthesized by solution methods. Analysis of the biological data and molecular modeling studies of these compounds, revealed an interesting trend in terms of the effects of the substituent at position two of the piperazine scaffold. Three different solid-phase protocols were explored toward the development of a combinatorial library of this type of compounds, which may facilitate future SAR studies.This item was digitized from a paper original and/or a microfilm copy. If you need higher-resolution images for any content in this item, please contact us at [email protected] file replaced with corrected file September 2023
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