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‣ Crystallization and preliminary X-ray diffraction analysis of importin-alpha acomplexed with NLS peptidomimetics

Fontes, MRM; Teh, T.; Riell, R. D.; Park, S. B.; Standaert, R. E.; Kobe, B.
Fonte: Elsevier B.V. Publicador: Elsevier B.V.
Tipo: Artigo de Revista Científica Formato: 9-13
Português
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Importin-alpha is the nuclear import receptor that recognizes cargo proteins with nuclear localization sequences (NLSs). Tile study of NLS peptidomimetics can provide a better understanding of the requirements for the molecular recognition of cargo proteins by importin-alpha, and potentially engender a large number of applications in medicine. Importin-a was crystallized with a set of six NLS peptidomimetics, and X-ray diffraction data were collected in the range 2.1-2.5 angstrom resolution. Preliminary electron density calculations show that the ligands are present in the crystals. (c) 2005 Elsevier B.V All rights reserved.

‣ Inhibition of dipeptidyl peptidase IV by fluoroolefin-containing N-peptidyl-O-hydroxylamine peptidomimetics

Lin, Jian; Toscano, Paul J.; Welch, John T.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 24/11/1998 Português
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Dipeptidyl peptidase IV (EC 3.4.14.5; DPP IV), also known as the leukocyte differentiation antigen CD26 when found as an extracellular membrane-bound proline specific serine protease, cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline residue in the penultimate position. Here we report that known (Z)-Ala-ψ[CF=C]-Pro dipeptide isosteres 1 and 2, which contain O-acylhydroxylamines, were isolated as diastereomeric pairs u-1, l-1, and l-2. The effect of each diastereomeric pair as an inhibitor of human placental dipeptidyl peptidase DPP IV has been examined. The inhibition of DPP IV by these compounds is rapid and efficient. The diastereomeric pair u-1 exhibits very potent inhibitory activity with a Ki of 188 nM. Fluoroolefin containing N-peptidyl-O-hydroxylamine peptidomimetics, by virtue of their inhibitory potency and stability, are superior to N-peptidyl-O-hydroxylamine inhibitors derived from an Ala-Pro dipeptide.

‣ High throughput synthesis of peptides and peptidomimetics

HRUBY, VICTOR J.; VAGNER, JOSEF
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2006 Português
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Peptide synthesis has been developed into one of the most efficient synthetic procedures in organic chemistry. The problems of orthogonal functional group protection and amide bond formation without racemization have been developed in a number of ingenious strategies. Optimization, in particular, has been achieved in stepwise solid phase synthesis. This in turn made possible the development of combinatorial synthesis allowing the synthesis of millions of peptide compounds of high purity in a few days. A variety of methodologies and strategies have been developed and continue to be developed to determine structures and to evaluate peptides and peptidomimetics. The development of methods for solid phase synthesis of a variety of organic and inorganic structures using similar strategies as in peptide synthesis are being vigorously pursued. However, existing instrumentation and technology is not sufficient to cover current demands for peptides, and thus new approaches and technologies for cost-effective synthesis of peptide arrays are needed.

‣ Synthesis of Isopeptide Epoxide Peptidomimetics

Majumdar, Debatosh; Alexander, Matthew D.; Coward, James K.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 16/01/2009 Português
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Two epoxide-containing peptidomimetics of the isopeptide, glutamyl-γ-glutamate, have been synthesized via a route that should be generally applicable to the synthesis of isopeptide analogs in which an oxirane replaces the scissile peptide bond. Enzymes that catalyze the hydrolysis of peptides and isopeptides are often susceptible to inactivation by electrophilic substrate analogs. In this research, an epoxide was installed as an electrophilic replacement of the scissile isopeptide bond. The C-terminal glutamyl mimic was accessed by the stereospecific synthesis of suitably substituted cyclopentenes as surrogates for either the l- or d- enantiomer. The enantiomeric cyclopentenes were further elaborated to incorporate an appended sulfone that was reacted with a suitably protected glutamyl-γ-semialdehyde in a Julia-Kocienski olefination reaction. This olefination afforded predominantly the desired E-olefin isosteres of l-glutamyl-γ-d-glutamate and l-glutamyl-γ-l-glutamate, following which peracid-mediated epoxidation and deprotection provided the epoxide-containing peptidomimetics, 4 and 5.

‣ Allosteric Modulation of the Dopamine D2 Receptor by Pro-Leu-Gly-NH2 Peptidomimetics Constrained in Either a Polyproline II Helix or a Type II β-Turn Conformation

Raghavan, Bhooma; Skoblenick, Kevin J.; Bhagwanth, Swapna; Argintaru, Niran; Mishra, Ram K.; Johnson, Rodney L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 09/04/2009 Português
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Type II β-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH2 (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the dopamine receptor, while the corresponding diastereoisomeric compounds 1b and 3b provided the first PLG peptidomimetics with the ability to decrease the binding of agonists to the dopamine receptor. The positive allosteric modulating activity of 3a supported the hypothesis that a polyproline II helix conformation is the bioactive conformation for the PLG analogue Pro-Pro-Pro-NH2. The results also show that a change in the bridgehead chirality of the 5.6.5 scaffold brings about opposite effects in terms of the modulation of the dopamine receptor.

‣ A Combinatorial Approach for the Design of Complementarity-determining Region-derived Peptidomimetics with in Vitro Anti-tumoral Activity*

Timmerman, Peter; Barderas, Rodrigo; Desmet, Johan; Altschuh, Danièle; Shochat, Susana; Hollestelle, Martine J.; Höppener, Jo W. M.; Monasterio, Alberto; Casal, J. Ignacio; Meloen, Rob H.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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The great success of therapeutic monoclonal antibodies has fueled research toward mimicry of their binding sites and the development of new strategies for peptide-based mimetics production. Here, we describe a new combinatorial approach for the production of peptidomimetics using the complementarity-determining regions (CDRs) from gastrin17 (pyroEGPWLEEEEEAYGWMDF-NH2) antibodies as starting material for cyclic peptide synthesis in a microarray format. Gastrin17 is a trophic factor in gastrointestinal tumors, including pancreatic cancer, which makes it an interesting target for development of therapeutic antibodies. Screening of microarrays containing bicyclic peptidomimetics identified a high number of gastrin binders. A strong correlation was observed between gastrin binding and overall charge of the peptidomimetic. Most of the best gastrin binders proceeded from CDRs containing charged residues. In contrast, CDRs from high affinity antibodies containing mostly neutral residues failed to yield good binders. Our experiments revealed essential differences in the mode of antigen binding between CDR-derived peptidomimetics (Kd values in micromolar range) and the parental monoclonal antibodies (Kd values in nanomolar range). However, chemically derived peptidomimetics from gastrin binders were very effective in gastrin neutralization studies using cell-based assays...

‣ A Systems Biology Approach to Dissection of the Effects of Small Bicyclic Peptidomimetics on a Panel of Saccharomyces cerevisiae Mutants*

Stefanini, Irene; Trabocchi, Andrea; Marchi, Emmanuela; Guarna, Antonio; Cavalieri, Duccio
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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In recent years, an approach called “chemical genetics” has been adopted in drug research to discover and validate new targets and to identify and optimize leads by high throughput screening. In this work, we tested the ability of a library of small peptidomimetics to induce phenotypic effects with functional implications on a panel of strains of the budding yeast Saccharomyces cerevisiae, both wild type and mutants, for respiratory function and multidrug resistance. Further elucidation of the function of these peptidomimetics was assessed by testing the effects of the compound with the most prominent inhibitory activity, 089, on gene expression using DNA microarrays. Pathway analysis showed the involvement of such a molecule in inducing oxidative damage through alterations in mitochondrial functions. Transcriptional experiments were confirmed by increased levels of ROS and activation of mitochondrial membrane potential. Our results demonstrate the influence of a functional HAP1 gene in the performance of S. cerevisiae as a model system.

‣ Crystal structures of HLA-A*0201 complexed with Melan-A/MART-126(27L)-35 peptidomimetics reveal conformational heterogeneity and highlight degeneracy of T cell recognition◊

Douat-Casassus, Céline; Borbulevych, Oleg; Tarbe, Marion; Gervois, Nadine; Jotereau, Francine; Baker, Brian M.; Quideau, Stéphane
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 14/10/2010 Português
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There is growing interest in using tumor associated antigens presented by class-I major histocompatibility complex (MHC-I) proteins as cancer vaccines. As native peptides are poorly stable in biological fluids, researchers have sought to engineer synthetic peptidomimetics with greater biostability. Here, we demonstrate that antigenic peptidomimetics of the Melan-A/MART-126(27L)-35 melanoma antigen adopt strikingly different conformations when bound to MHC-I, highlighting the degeneracy of T cell recognition and revealing the challenges associated with mimicking native peptide conformation.

‣ Universal Peptidomimetics

Ko, Eunhwa; Liu, Jing; Perez, Lisa M.; Lu, Genliang; Schaefer, Amber; Burgess, Kevin
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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This paper concerns peptidomimetic scaffolds that can present side-chains in conformations resembling those of amino acids in secondary structures without incurring excessive entropic or enthalpic penalties. Compounds of this type are referred to here as minimalist mimics. The core hypothesis of this paper is that small sets of such scaffolds can be designed to analog local pairs of amino acids (including non-contiguous ones) in any secondary structure, ie they are universal peptidomimetics. To illustrate this concept we designed a set of four peptidomimetic scaffolds (1 – 4). Libraries based on these were made bearing side-chains corresponding to many of the protein-derived amino acids. Modeling experiments were performed to give an indication of kinetic and thermodynamic accessibilities of conformations that can mimic secondary structures. Together peptidomimetics based on scaffolds 1 – 4 can adopt conformations that resemble almost any combination of local amino acid side-chains in any secondary structure. Universal peptidomimetics of this kind are likely to be most useful in the design of libraries for high throughput screening against diverse targets. Consequently, data arising from submission of these molecules to the NIH Molecular Libraries Small Molecule Repository (MLSMR) is outlined.

‣ Structure-activity relationship of conformationally constrained peptidomimetics for antiproliferative activity in HER2-overexpressing breast cancer cell lines

Banappagari, Sashikanth; Ronald, Sharon; Satyanarayanajois, Seetharama D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/01/2011 Português
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Human epidermal growth factor receptor 2 (HER2) is a member of the human epidermal growth factor receptor kinases and is involved in a signaling cascade for cell growth and differentiation. It is well established that HER2-mediated heterodimerization has important implications in cancer. Deregulation of signaling pathways and overexpression of HER2 is known to occur in cancer cells, indicating the role of HER2 in tumorigenesis. Therefore, blocking HER2-mediated signaling has potential therapeutic value. We have designed several peptidomimetics to inhibit HER2-mediated signaling for cell growth. One of the compounds (compound 5, Arg-[3-amino-3(1-napthyl)-propionic acid]-Phe) exhibited antiproliferative activity with IC50 values in the nanomolar to micromolar range in breast cancer cell lines. To further investigate the structure-activity relationship of the compounds, various analogs of compound 5 were designed. Conformational constraints were initiated in the peptidomimetic with introduction of a Pro residue in the peptidomimetic sequence. Results of antiproliferative activity indicated that analogs of compound 5 with C-and N-terminal ends capped (compound 16) and compound 9 with Asp at the C-terminal exhibited antiproliferative activity in the lower micromolar range against breast cancer cell lines. Introduction of conformational constraints such as Pro residue in the sequence or cyclization did not enhance the activity of the peptidomimetic. Competitive binding studies were carried out to evaluate the binding of potent peptidomimetics to HER2-overexpressing cancer cell lines. Results indicated that compounds exhibiting antiproliferative activity in breast cancer cell lines bind to the cells that overexpress HER2 protein.

‣ Manipulating Connexin Communication Channels: Use of Peptidomimetics and the Translational Outputs

Evans, W. Howard; Bultynck, Geert; Leybaert, Luc
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
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Gap junctions are key components underpinning multicellularity. They provide cell to cell channel pathways that enable direct intercellular communication and cellular coordination in tissues and organs. The channels are constructed of a family of connexin (Cx) membrane proteins. They oligomerize inside the cell, generating hemichannels (connexons) composed of six subunits arranged around a central channel. After transfer to the plasma membrane, arrays of Cx hemichannels (CxHcs) interact and couple with partners in neighboring attached cells to generate gap junctions. Cx channels have been studied using a range of technical approaches. Short peptides corresponding to sequences in the extra- and intracellular regions of Cxs were used first to generate epitope-specific antibodies that helped studies on the organization and functions of gap junctions. Subsequently, the peptides themselves, especially Gap26 and -27, mimetic peptides derived from each of the two extracellular loops of connexin43 (Cx43), a widely distributed Cx, have been extensively applied to block Cx channels and probe the biology of cell communication. The development of a further series of short peptides mimicking sequences in the intracellular loop, especially the extremity of the intracellular carboxyl tail of Cx43...

‣ An Index for Characterization of Natural and Non-Natural Amino Acids for Peptidomimetics

Liang, Guizhao; Liu, Yonglan; Shi, Bozhi; Zhao, Jun; Zheng, Jie
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 23/07/2013 Português
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Bioactive peptides and peptidomimetics play a pivotal role in the regulation of many biological processes such as cellular apoptosis, host defense, and biomineralization. In this work, we develop a novel structural matrix, Index of Natural and Non-natural Amino Acids (NNAAIndex), to systematically characterize a total of 155 physiochemical properties of 22 natural and 593 non-natural amino acids, followed by clustering the structural matrix into 6 representative property patterns including geometric characteristics, H-bond, connectivity, accessible surface area, integy moments index, and volume and shape. As a proof-of-principle, the NNAAIndex, combined with partial least squares regression or linear discriminant analysis, is used to develop different QSAR models for the design of new peptidomimetics using three different peptide datasets, i.e., 48 bitter-tasting dipeptides, 58 angiotensin-converting enzyme inhibitors, and 20 inorganic-binding peptides. A comparative analysis with other QSAR techniques demonstrates that the NNAAIndex method offers a stable and predictive modeling technique for in silico large-scale design of natural and non-natural peptides with desirable bioactivities for a wide range of applications.

‣ Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

Koopmanschap, Gijs; Ruijter, Eelco; Orru, Romano VA
Fonte: Beilstein-Institut Publicador: Beilstein-Institut
Tipo: Artigo de Revista Científica
Publicado em 04/03/2014 Português
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In the recent past, the design and synthesis of peptide mimics (peptidomimetics) has received much attention. This because they have shown in many cases enhanced pharmacological properties over their natural peptide analogues. In particular, the incorporation of cyclic constructs into peptides is of high interest as they reduce the flexibility of the peptide enhancing often affinity for a certain receptor. Moreover, these cyclic mimics force the molecule into a well-defined secondary structure. Constraint structural and conformational features are often found in biological active peptides. For the synthesis of cyclic constrained peptidomimetics usually a sequence of multiple reactions has been applied, which makes it difficult to easily introduce structural diversity necessary for fine tuning the biological activity. A promising approach to tackle this problem is the use of multicomponent reactions (MCRs), because they can introduce both structural diversity and molecular complexity in only one step. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs) are most relevant for the synthesis of peptidomimetics because they provide peptide-like products. However, these IMCRs usually give linear products and in order to obtain cyclic constrained peptidomimetics...

‣ Peptidomimetics as a new generation of antimicrobial agents: current progress

Méndez-Samperio, Patricia
Fonte: Dove Medical Press Publicador: Dove Medical Press
Tipo: Artigo de Revista Científica
Publicado em 30/08/2014 Português
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Antibiotic resistance is an increasing public health concern around the world. Rapid increase in the emergence of multidrug-resistant bacteria has been the target of extensive research efforts to develop a novel class of antibiotics. Antimicrobial peptides (AMPs) are small cationic amphiphilic peptides, which play an important role in the defense against bacterial infections through disruption of their membranes. They have been regarded as a potential source of future antibiotics, owing to a remarkable set of advantageous properties such as broad-spectrum activity, and they do not readily induce drug-resistance. However, AMPs have some intrinsic drawbacks, such as susceptibility to enzymatic degradation, toxicity, and high production cost. Currently, a new class of AMPs termed “peptidomimetics” have been developed, which can mimic the bactericidal mechanism of AMPs, while being stable to enzymatic degradation and displaying potent activity against multidrug-resistant bacteria. This review will focus on current findings of antimicrobial peptidomimetics. The potential future directions in the development of more potent analogs of peptidomimetics as a new generation of antimicrobial agents are also presented.

‣ Peptides and peptidomimetics as immunomodulators

Gokhale, Ameya S; Satyanarayanajois, Seetharama
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2014 Português
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Peptides and peptidomimetics can function as immunomodulating agents by either blocking the immune response or stimulating the immune response to generate tolerance. Knowledge of B- or T-cell epitopes along with conformational constraints is important in the design of peptide-based immunomodulating agents. Work on the conformational aspects of peptides, synthesis and modified amino acid side chains have contributed to the development of a new generation of therapeutic agents for autoimmune diseases and cancer. The design of peptides/peptidomimetics for immunomodulation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus and HIV infection is reviewed. In cancer therapy, peptide epitopes are used in such a way that the body is trained to recognize and fight the cancer cells locally as well as systemically.

‣ Synthesis and elaboration of peptidomimetic units

RAMADORI, FEDERICO
Fonte: La Sapienza Universidade de Roma Publicador: La Sapienza Universidade de Roma
Tipo: Tese de Doutorado
Português
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Retro-peptides are peptidomimetics that present the direction of the amino acidic sequence reversed. A classical retro modification can be obtained by the introduction of the malonyl unit followed by a gem-diaminic unit, that can result in an increase of proteolysis resistance of the related parent peptide, retarding degradation and consequently enhancing therapeutic efficacy.This thesis aims at developing synthetic stategies to synthesize new interesting building blocks for the construction of peptidomimetics containing a retro modification.In this field Meldrum’s acid is recently reported as a useful scaffold to obtain non-symmetric disubstituted malonamides rAA-mGly-AA′ as building blocks for the synthesis of retro-peptides. The attention has been turned towards the synthetic elaboration of different rAA-mGly-AA′ with the aim of introducing, into the malonamide backbone, the olefinic moiety by a Knoevenagel condensation, obtaining correspondig malonyl dehydro peptides MDHPs.The investigation of a further elaboration was carried out to obtain the corresponding epoxy and aziridino peptides,interesting building blocks containing electrophilic sites known to react with nucleophilic amino acids within the active site of proteases. Starting from L-amino acids...

‣ 1,2,3-triazoles in peptidomimetic chemistry

Pedersen, D.; Abell, A.
Fonte: Wiley-V C H Verlag GMBH Publicador: Wiley-V C H Verlag GMBH
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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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.; Daniel Sejer Pedersen and Andrew Abell

‣ Design and synthesis and testing of conformationally constrained peptidomimetics.

Duncan, Joanna Kimberley
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2013 Português
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This thesis describes the design, synthesis and testing of peptidomimetics pre-organised into bioactive conformations. Chapter One introduces the concept of peptidomimetics, their importance as potential pharmaceuticals. The concept of constraining a compound into a bioactive conformation (α-helix, β-turn or β-strand) by incorporation of a ring or bridge is discussed. The technique of ring closing metathesis as a strategy for cyclisation of peptidomimetics is introduced. Chapter Two surveys β-turn mimics comprised of β-amino acids. The synthesis of novel cyclic peptidomimetics comprised of β-amino acids (cyclised by ring closing metathesis) is presented. Three of the cyclic dipeptides were predicted (through in silico conformational searches) to adopt a β-turn motif. Cyclic scaffolds 2.62, 2.65 and 2.66 were each incorporated into a tri-peptide to give 2.68, 2.69 and 2.70. The propensity of each tri-peptide to adopt a β-turn motif was investigated by 1H NMR. There is strong evidence that 2.70 has a β-turn geometry based on the presence of an intra-molecular hydrogen bond between the i and i+3 residues. Chapter Three introduces cysteine protease calpain II as the primary biological target for this thesis. Calpain is implicated in cataract formation and its inhibition is a logical approach to cataract prevention. Proteases are known to...

‣ Syntheses, bioactivities and conformations of peptidomimetics containing 2,3-methanoamino acids

Ho, Kwok-Kan
Fonte: Universidade Rice Publicador: Universidade Rice
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Asymmetric syntheses of E- and Z-2,3-methanomethionine (ie E- and Z-cyclo-Met), protected Z-2,3-methanoarginine, and Z-2,3-methanoaspartic acid derivatives have been developed. These functionalized 2,3-methanoamino acids were prepared from a common intermediate: 1- ((tert-butoxy)carbonyl) -2-oxo-3-oxa-bicyclo (3.1.0) hexane. Peptidomimetics containing some of these 2,3-methanoamino acids mentioned above were synthesized via a solid phase approach. The Met$sp2$ in neuropeptide Phe-Met-Arg-Phe-NH$sb2$ (FMRF-NH$sb2$, one letter code for amino acids) was systematically replaced by each of the isomers of cyclo-Met giving four peptidomimetics, namely F${$2S,3R-cyclo-M$}$RF-NH$sb2$, F${$2R,3S-cyclo-M$}$RF-NH$sb2$, F${$2S,3S-cyclo-M$}$RF-NH$sb2$ and F${$2R,3R-cyclo-M$}$RF-NH$sb2$. A peptidomimetic containing two 2,3-methanoamino acids substituted in the 2 and 4 positions (ie F${$2S,3S-cyclo-M$}$R${$2R,3R-cyclo-F$}$-NH$sb2$) was also prepared. Generally, 2,3-methanoamino acids are compatible with solid phase chemistry, although they are more sterically hindered than their corresponding natural amino acids. Anti-opiate activities, and proteolytic stabilities of the peptidomimetics were studied. The peptidomimetics were more active (in vivo) than the FMRF-NH$sb2$ but bind less strongly to the appropriate receptor sites. This observation seems to be related to the enhanced bio-availability of the peptidomimetics...

‣ Development of Anti-EGF Receptor Peptidomimetics (AERP) as Tumor Imaging Agent

Ponde, Datta E.; Su, ZiFen; Berezov, Alan; Zhang, Hongtao; Alavi, Abbas; Greene, Mark I.; Murali, Ramachandran
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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EGFR is over-expressed in several solid tumors including breast, prostate, pancreas and lung cancers and is correlated to the metastasic potential of the tumor. Anti-EGFR receptor-binding peptidomimetics (AERP) were examined to assess the small molecule's potential use as tumor-specific imaging agents. The aim of this work was to design and characterize the binding specificity of the radiolabeled peptidomimetics to EGFR over-expressing cell lysate and to A431 xenograft tumors. Our newly designed peptidomimetic, AERP, was conjugated to DTPA and labeled with 99mTc. The in vivo tumor accumulation of [99mTc] DTPA-AERP-2 was 1.6 ± 0.1 %ID/g and tumor to muscle ratio was 5.5. Our studies suggest that this novel peptidomimetic, AERP-2, warrants further development as an EGFR-specific tumor-imaging agent.