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Rodney L Johnson - One of the best experts on this subject based on the ideXlab platform.
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synthesis and dopamine receptor modulating activity of 3 substituted γ lactam Peptidomimetics of l prolyl l leucyl glycinamide
Journal of Medicinal Chemistry, 2003Co-Authors: Kristine Dolbeare, Ram K Mishra, Giuseppe F Pontoriero, Suresh K Gupta, Rodney L JohnsonAbstract:γ-Lactam Peptidomimetic 2 of Pro-Leu-Gly-NH2 (PLG) was substituted at the 3-position with isobutyl, butyl, and benzyl moieties to give the PLG Peptidomimetics 3−5, respectively. These compounds were synthesized to test the hypothesis that attaching a hydrophobic moiety to the lactam ring to mimic the isobutyl side chain of the leucyl residue of PLG would increase the dopamine receptor modulating activity of such Peptidomimetics. These Peptidomimetics were tested for their ability to enhance the binding of [3H]-N-propylnorapomorphine to dopamine receptors isolated from bovine striatal membranes. The rank order of effectiveness of the 3-substituent was benzyl > n-butyl > isobutyl > H.
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synthesis and dopamine receptor modulating activity of substituted bicyclic thiazolidine lactam Peptidomimetics of l prolyl l leucyl glycinamide
Journal of Medicinal Chemistry, 1999Co-Authors: Ehab Khalil, Ashish Pradhan, William H Ojala, William B Gleason, Ram K Mishra, Rodney L JohnsonAbstract:6-Substituted bicyclic thiazolidine lactam Peptidomimetics of Pro-Leu-Gly-NH(2) (1) were synthesized to test the hypothesis that incorporation of a hydrophobic side chain into the bicyclic thiazolidine lactam scaffold would further enhance the dopamine receptor modulating activity of such Peptidomimetics. The substituents employed were the isobutyl, butyl, and benzyl groups to give Peptidomimetics 3-5, respectively. These Peptidomimetics were evaluated in vivo as modulators of apomorphine-induced rotational behavior in the 6-hydroxydopamine-lesioned rat model of hemiparkinsonism and were compared with the unsubstituted bicyclic thiazolidine lactam Pro-Leu-Gly-NH(2) Peptidomimetic 2. Peptidomimetics 3-5 each affected rotational behavior in a bell-shaped dose-response relationship producing maximal increases of 44% (1 microgram/kg,ip), 56% (0.1 microgram/kg,ip), and 30% (1 microgram/kg, ip), respectively. In comparison, unsubstituted Peptidomimetic 2 increased rotational behavior by only 23% at a dose of 0.1 microgram/kg, ip.
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Modulatory effects of PLG and its Peptidomimetics on haloperidol-induced catalepsy in rats.
Peptides, 1999Co-Authors: Willard J. Costain, Ram K Mishra, Adam T Buckley, Margaret C. Evans, Rodney L JohnsonAbstract:Abstract A behavioral model of dopaminergic function in the rat was used to examine the anticataleptic effects of l -prolyl- l -leucyl-glycinamide (PLG) and Peptidomimetic analogs of PLG. Administration of 1 mg/kg PLG intraperitoneally significantly attenuated haloperidol (1 mg/kg)-induced catalepsy (as measured by the standard horizontal bar test), whereas doses of 0.1 and 10 mg/kg PLG did not. Eight synthetic PLG Peptidomimetics (Cα, α-dialkylated glycyl residues with lactam bridge constraint [ 1–4 ] and without [ 5–8 ]) were tested in the same manner (at a dose of 1 μg/kg) and categorized according to their activity, i.e. very active ( 5 ), moderately active ( 2, 3, 4, and 6 ), and inactive ( 1, 7, and 8 ). The catalepsy-reversal action of the diethylglycine-substituted Peptidomimetic 5 was examined further and found to exhibit a U-shaped dose–response effect with an optimal dose of 1 μg/kg. The similarity between the effects of PLG and the synthetic Peptidomimetics suggests a common mechanism of action. Finally, the synthetic Peptidomimetics examined here, particularly Peptidomimetic 5 , were more effective than PLG in attenuating haloperidol-induced catalepsy.
Shaomeng Wang - One of the best experts on this subject based on the ideXlab platform.
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high affinity small molecule Peptidomimetic inhibitors of mll1 wdr5 protein protein interaction
Journal of the American Chemical Society, 2013Co-Authors: Hacer Karatas, Yali Dou, Liu Liu, Yong Chen, Denzil Bernard, Ming Lei, Elizabeth C. Townsend, Fang Cao, Shaomeng WangAbstract:Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein–protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of Peptidomimetics to target the MLL1/WDR5 interaction based upon −CO-ARA-NH–, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity Peptidomimetics, which bind to WDR5 with Ki < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent Peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such Peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively de...
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High-Affinity, Small-Molecule Peptidomimetic Inhibitors of MLL1/WDR5 Protein–Protein Interaction
Journal of the American Chemical Society, 2012Co-Authors: Hacer Karatas, Yali Dou, Liu Liu, Yong Chen, Denzil Bernard, Ming Lei, Elizabeth C. Townsend, Fang Cao, Shaomeng WangAbstract:Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase, and targeting the MLL1 enzymatic activity has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. The MLL1/WDR5 protein–protein interaction is essential for MLL1 enzymatic activity. In the present study, we designed a large number of Peptidomimetics to target the MLL1/WDR5 interaction based upon −CO-ARA-NH–, the minimum binding motif derived from MLL1. Our study led to the design of high-affinity Peptidomimetics, which bind to WDR5 with Ki < 1 nM and function as potent antagonists of MLL1 activity in a fully reconstituted in vitro H3K4 methyltransferase assay. Determination of co-crystal structures of two potent Peptidomimetics in complex with WDR5 establishes their structural basis for high-affinity binding to WDR5. Evaluation of one such Peptidomimetic, MM-102, in bone marrow cells transduced with MLL1-AF9 fusion construct shows that the compound effectively de...
Andrew D. Abell - One of the best experts on this subject based on the ideXlab platform.
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1,2,3-Triazoles in Peptidomimetic Chemistry
ChemInform, 2011Co-Authors: Daniel Sejer Pedersen, Andrew D. AbellAbstract:Review: [triazoles prepared by cycloadditions reactions as both “linear” and “bent” Peptidomimetics, use of triazoles to define the geometry and properties of a Peptidomimetic; 83 refs.]
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1,2,3‐Triazoles in Peptidomimetic Chemistry
European Journal of Organic Chemistry, 2011Co-Authors: Daniel Sejer Pedersen, Andrew D. AbellAbstract:The ability to synthesise small Peptidomimetics that mimic the secondary structure of proteins is an ever expanding area of research directed at sourcing new medicinal agents and biological probes. A significant current challenge is to mimic protein epitopes under physiological conditions using small Peptidomimetics that are easy to prepare. The copper- and ruthenium-catalysed Huisgen cycloaddition reactions provide such a general synthetic method, with the resulting 1,2,3-triazoles being good peptide bond mimics. The ability to prepare both 1,4- and 1,5-substituted 1,2,3-triazoles under these chemically benign conditions provides both "linear" and "bent" Peptidomimetics. Examples of the use of 1,2,3-triazoles to define the geometry and properties of a Peptidomimetic abound. This review highlights such successes but also describes a number of failures in order to guide and inspire future efforts of chemists in this area.
Andrea Trabocchi - One of the best experts on this subject based on the ideXlab platform.
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Peptidomimetic toolbox for drug discovery.
Chemical Society reviews, 2020Co-Authors: Elena Lenci, Andrea TrabocchiAbstract:The art of transforming peptides into drug leads is still a dynamic and fertile field in medicinal chemistry and drug discovery. Peptidomimetics can respond to peptide limitations by displaying higher metabolic stability, good bioavailability and enhanced receptor affinity and selectivity. Various synthetic strategies have been developed over the years in order to modulate the conformational flexibility and the peptide character of Peptidomimetic compounds. This tutorial review aims to outline useful tools towards Peptidomimetic design, spanning from local modifications, global restrictions and the use of secondary structure mimetics. Selected successful examples of each approach are presented to document the relevance of Peptidomimetics in drug discovery.
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Principles and applications of small molecule Peptidomimetics
Small Molecule Drug Discovery, 2020Co-Authors: Andrea TrabocchiAbstract:Abstract Peptidomimetic chemistry is a well-established approach for the generation of small-molecule-based drugs acting as enzyme inhibitors or receptor ligands. Since the introduction of this concept in the 1990s, this approach is still relevant in drug discovery, given the significance and importance of developing drugs starting from bioactive peptides. In fact, the generation of small molecule Peptidomimetics consists of reducing the conformational flexibility and the peptide character to improve the potency and selectivity, and to achieve hit compounds with improved bioactivity and pharmacokinetics profile. The synthetic approaches toward Peptidomimetics have evolved over the years, spanning from combinatorial chemistry to solid-phase synthesis and heterocyclic chemistry. This chapter aims to give an overview of Peptidomimetics and their classification based on common structural features, and to discuss the key synthetic approaches to achieve bioactive compounds of “Peptidomimetic nature.” Also, the case study of HIV protease inhibitors is to document the relevance of Peptidomimetics in drug discovery.
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cyclic rgd Peptidomimetics containing 4 and 5 amino cyclopropane pipecolic acid cpa templates as dual αvβ3 and α5β1 integrin ligands
Bioorganic & Medicinal Chemistry, 2016Co-Authors: Lorenzo Sernissi, Andrea Trabocchi, Dina Scarpi, Francesca Bianchini, Ernesto G OcchiatoAbstract:4-Amino- and 5-amino-cyclopropane pipecolic acids (CPAs) with cis relative stereochemistry between the carboxylic and amino groups were used as templates to prepare cyclic Peptidomimetics containing the RGD sequence as possible integrin binders. The Peptidomimetic c(RGD8) built on the 5-amino-CPA displayed an inhibition activity (IC50=2.4nM) toward the αvβ3 integrin receptor (expressed in M21 human melanoma cell line) comparable to that of the most potent antagonists reported so far and it was ten times more active than the corresponding antagonist c(RGD7) derived from the isomeric 4-amino-CPA. Both compounds were also nanomolar ligands of the α5β1 integrin (expressed in human erythroleukemia cell line K562). These results suggest that the CPA-derived templates are suitable for the preparation of dual αvβ3 and α5β1 ligands to suppress integrin-mediated events as well as for targeted drug delivery in cancer therapy.
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Chemical genetics approach to drug discovery by diversity-oriented synthesis (DOS) of Peptidomimetics*
Pure and Applied Chemistry, 2011Co-Authors: Andrea Trabocchi, Duccio Cavalieri, Antonio GuarnaAbstract:Chemical genetics, which relies on selecting small molecules for their ability to induce a biological phenotype or to interact with a particular gene product, is a new power- ful tool for lead generation in drug discovery. Accordingly, diversity-oriented synthesis (DOS) of small-molecule Peptidomimetics gives access to collections of new chemotypes bearing high structural diversity. Biological evaluation using cell growth as a phenotypic screening on Saccharomyces cerevisiae deletant strains is a powerful tool to identify new chemotypes as hit compounds in the discovery of new antifungal and anticancer agents, and also in the dissection of their mode of action. Our contribution in this field focused on the screening of morpholine-based Peptidomimetic collections toward yeast deletant strains, which provided the identification of new chemotypes involved in mitochondria metabolism and respiration.
Lucie Morere - One of the best experts on this subject based on the ideXlab platform.
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Disrupting the CD95–PLCγ1 interaction prevents Th17-driven inflammation
Nature Chemical Biology, 2018Co-Authors: Amanda Poissonnier, Jean-philippe Guégan, Ha Thanh Nguyen, Daniel Best, Nicolas Levoin, Guennadi Kozlov, Kalle Gehring, Raphael Pineau, Florence Jouan, Lucie MorereAbstract:The HIV protease inhibitor ritonavir targets the calcium-inducing domain (CID) of CD95 to block interactions with PLCγ1. Peptidomimetics targeting the CD95 CID prevents accumulation of inflammatory Th17 cells observed in systemic lupus erythematosus. CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca^2+ response via docking of PLCγ1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95–PLCγ1 interaction. A structure–activity relationship approach highlighted that ritonavir is a Peptidomimetic that shares structural characteristics with CID with respect to docking to PLCγ1. Thus, we synthesized CID Peptidomimetics abrogating both the CD95-driven Ca^2+ response and transmigration of Th17 cells. Injection of ritonavir and the CID Peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients.
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Disrupting the CD95-PLC gamma 1 interaction prevents Th17-driven inflammation
Nature Chemical Biology, 2018Co-Authors: Amanda Poissonnier, Jean-philippe Guégan, Ha Thanh Nguyen, Daniel Best, Nicolas Levoin, Guennadi Kozlov, Kalle Gehring, Raphael Pineau, Florence Jouan, Lucie MorereAbstract:CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca2+ response via docking of PLC gamma 1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLC gamma 1 interaction. A structure-activity relationship approach highlighted that ritonavir is a Peptidomimetic that shares structural characteristics with CID with respect to docking to PLC gamma 1. Thus, we synthesized CID Peptidomimetics abrogating both the CD95-driven Ca2+ response and transmigration of Th17 cells. Injection of ritonavir and the CID Peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients.
