Publications

2021
Photolabile Protecting Group-Mediated Synthesis of 2-Deoxy-Glycosides
Xiaoqian Li, Zhi Ma, Rongkun Liu, Mattan Hurevich, and You Yang. 9/1/2021. “Photolabile Protecting Group-Mediated Synthesis of 2-Deoxy-Glycosides.” Chinese Journal of Chemistry, n/a, n/a. Abstract

Main observation and conclusion A green and efficient photolabile protecting group (PPG)-mediated glycosidation approach for the synthesis of 2-deoxy-glycosides is reported. By employing ortho-nitrobenzyl carbonate (oNBC) as PPG, N,N-dimethylformamide (DMF)-modulated SPhosAuNTf2-promoted glycosidation with per-oNBC-protected 2-deoxy-glycosyl ynenoates afforded the 2-deoxy-glycosides with moderate to excellent α-selectivities presumably depending on the reactivities of the acceptor alcohols. Based on the PPG-mediated glycosidation approach, oligosaccharides with three to six oNBC groups were effectively achieved. The multiple oNBC groups in the 2-deoxy-glycosides were completely cleaved by irradiation at 365 nm, resulting in the desired 2-deoxy-glycosides in an efficient manner without affecting the common alkyne, alkene and azide functional groups and the traditional protecting groups on the aglycones. This article is protected by copyright. All rights reserved.

 

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D. Ben Abba Amiel, I. Alshanski, and M. Hurevich. 2021. “Automated Oligosaccharide Synthesis: Development of the Glyconeer®.” In Comprehensive Glycoscience (Second Edition), edited by Joseph J. Barchi, Second Edition, Pp. 548-560. Oxford: Elsevier. Publisher's Version Abstract

Developing automated platforms is essential for accelerating the preparation of bioactive compound libraries. After a decade of biopolymer synthesis, it is clear that automating these processes was pivotal to the development of biochemistry and chemical biology for advancing medicinal chemistry and for providing new diagnoses and therapeutic tools. Synthesis of glycans and glycoconjugates is far more complicated than the other biopolymer families. Automating glycan synthesis has been a long and hard journey which is still ongoing. This chapter focuses on the development of a commercial platform, Glyconeer™, aimed to automate the synthesis of glycans. The design and process leading to the establishment of the current setup are described. The unique considerations required from a system that is suitable for glycan synthesis are the focus of the chapter. We explain how the selected setup architecture and its unique features comply with the unusual demands of automated solid phase synthesis of glycans. We will present the common modules, building blocks, and chemistries used by the synthesizer. Preparation, handling, and running of both software and hardware are presented from the user point of view. A critical view of the limitations and advantages of the system is aimed to provide a roadmap for future improvement.

Automated Synthesis of Heavily Phosphorylated Peptides
Dana Grunhaus, Assaf Friedler, and Mattan Hurevich. 2021. “Automated Synthesis of Heavily Phosphorylated Peptides.” European Journal of Organic Chemistry, 2021, 26, Pp. 3737-3742. Abstract

Abstract Multi phosphorylated peptides are key tools in understanding the biological roles of protein phosphorylation patterns. In this work, we focused on multi phosphorylated peptides with over four, clustered, phosphorylation sites that are termed herein heavily phosphorylated peptides (HPPs). The synthesis of heavily phosphorylated peptides is extremely difficult and requires the use of a wide temperature range. Standard peptide synthesizers are incapable of both cooling and heating, which impedes the automated synthesis of those peptides. Herein, we used the oligosaccharide synthesizer Glyconeer 2.1 to develop a protocol for the automated synthesis of heavily phosphorylated peptides. The Glyconeer 2.1 is able to both cool and heat, which enabled the development of highly controlled coupling and deprotection conditions that were used for the automated synthesis of four different heavily phosphorylated peptides with five or more, clustered, phosphorylation sites. Our approach paves the way for an easy automated synthesis of a variety of heavily phosphorylated peptides.

 

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Determining the structure and binding mechanism of oxytocin-Cu(2+) complex using paramagnetic relaxation enhancement NMR analysis
I. Alshanski, D. E. Shalev, S. Yitzchaik, and M. Hurevich. 2021. “Determining the structure and binding mechanism of oxytocin-Cu(2+) complex using paramagnetic relaxation enhancement NMR analysis.” J Biol Inorg Chem. Abstract

Oxytocin is a neuropeptide that binds copper ions in nature. The structure of oxytocin in interaction with Cu2+ was determined here by NMR, showing which atoms of the peptide are involved in binding. Paramagnetic relaxation enhancement NMR analyses indicated a binding mechanism where the amino terminus was required for binding and subsequently Tyr2, Ile3 and Gln4 bound in that order. The aromatic ring of Tyr2 formed a π-cation interaction with Cu2+. Oxytocin copper complex structure revealed by paramagnetic relaxation enhancement NMR analyses.

 

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Electrochemical biosensing platform based on complex biantennary N-glycan for detecting enzymatic sialylation processes
Israel Alshanski, Yonatan Sukhran, Evgeniy Mervinetsky, Carlo Unverzagt, Shlomo Yitzchaik, and Mattan Hurevich. 2021. “Electrochemical biosensing platform based on complex biantennary N-glycan for detecting enzymatic sialylation processes.” Biosensors and Bioelectronics, 172, Pp. 112762. Abstract

Sialylated glycans and glycoproteins are involved in cellular communication and are crucial for distinguishing between signal pathways. Sialylation levels and patterns modulate recognition events and are regulated by the enzymatic activity of sialyltransferases and neuraminidases. Abnormal activity of these enzymes is related to diseases such as cancer and viral infection. Monitoring these enzymatic activities offers valuable diagnostic tools. This work presents an impedimetric biosensing platform for following and detecting sialylation and desialylation processes. This platform is based on a native biantennary N-glycan substrate attached to a glassy carbon electrode. Changes in the molecular layer, as a result of enzymatic reactions, were detected by electrochemical impedance spectroscopy, displaying high sensitivity to the enzymatic surface reactions. Increase in the molecular layer roughness in response to the sialylation was visualized using atomic force microscopy. After enzymatic sialylation, the presence of sialic acid was confirmed using cyclic voltammetry by coupling of the redox active marker aminoferrocene. The sialylation showed selectivity toward the N-glycan compared to another glycan substrate. A time dependent sialylation was followed by electrochemical impedance spectroscopy, proving that the new system can be applied to evaluate the enzymatic kinetics. Our findings suggest that analyzing sialylation processes using this platform can become a useful tool for the detection of pathological states and pathogen invasion.

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The influence of surface proximity on photoswitching activity of stilbene-functionalized N-heterocyclic carbene monolayers
Shahar Dery, Israel Alshanski, Evgeniy Mervinetsky, Daniel Feferman, Shlomo Yitzchaik, Mattan Hurevich, and Elad Gross. 2021. “The influence of surface proximity on photoswitching activity of stilbene-functionalized N-heterocyclic carbene monolayers.” Chem. Commun., 57, Pp. 6233-6236. Abstract

Self-assembly of photo-responsive molecules is a robust technology for reversibly tuning the properties of functional materials. Herein, we probed the crucial role of surface–adsorbate interactions on the adsorption geometry of stilbene-functionalized N-heterocyclic carbenes (stilbene-NHCs) monolayers and its impact on surface potential. Stilbene-NHCs on Au film accumulated in a vertical orientation that enabled high photoisomerization efficiency and reversible changes in surface potential. Strong metal–adsorbate interactions led to flat-lying adsorption geometry of stilbene-NHCs on Pt film, which quenched the photo-isomerization influence on surface potential. It is identified that photo-induced response can be optimized by positioning the photo-active group in proximity to weakly-interacting surfaces.

 

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Non-covalently embedded oxytocin in alkanethiol monolayer as Zn2+ selective biosensor
J. Attia, S. Nir, E. Mervinetsky, D. Balogh, A. Gitlin-Domagalska, I. Alshanski, M. Reches, M. Hurevich, and S. Yitzchaik. 2021. “Non-covalently embedded oxytocin in alkanethiol monolayer as Zn2+ selective biosensor.” Scientific Reports, 11, 1. Abstract

Peptides are commonly used as biosensors for analytes such as metal ions as they have natural binding preferences. In our previous peptide-based impedimetric metal ion biosensors, a monolayer of the peptide was anchored covalently to the electrode. Binding of metal ions resulted in a conformational change of the oxytocin peptide in the monolayer, which was measured using electrochemical impedance spectroscopy. Here, we demonstrate that sensing can be achieved also when the oxytocin is non-covalently integrated into an alkanethiol host monolayer. We show that ion-binding cause morphological changes to the dense host layer, which translates into enhanced impedimetric signals compared to direct covalent assembly strategies. This biosensor proved selective and sensitive for Zn2+ ions in the range of nano- to micro-molar concentrations. This strategy offers an approach to utilize peptide flexibility in monitoring their response to the environment while embedded in a hydrophobic monolayer.

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2020
A. K. Kubowicz, K. Kustanovich, A. Gitlin-Domagalska, V. Yantchev, M. Hurevich, S. Yitzchaik, A. Jesorka, and I. Gozen. 2020. “Supported Model Membranes for Biosensing Applications - Optical Oxytocin Binding Assay.” Biophysical Journal, 118, 3, Pp. 232a-233a. Publisher's Version
The Breaking Beads Approach for Photocleavage from Solid Support
Yasmeen Bakhatan, Israel Alshanski, Dana Grunhaus, and Mattan Hurevich. 2020. “The Breaking Beads Approach for Photocleavage from Solid Support.” Organic & Biomolecular Chemistry. Abstract

Photocleavage from polystyrene beads is a pivotal reaction for solid phase synthesis that relies on photolabile linkers. Photocleavage from intact porous polystyrene beads is not optimal because light cannot penetrate into the beads and the surface area exposed to irradiation is limited. Thus, hazardous, technically challenging and expensive setups are used for photocleavage from intact beads. We developed a new concept in which grinding the beads during or prior to irradiation is employed as an essential part of the photocleavage process. By grinding the beads we are exposing more surface area to the light source, hence, photocleavage can be performed even using a simple benchtop LED setup. This approach proved very efficient for photocleavage of various model compounds including fully protected oligosaccharides.

 

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Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs
Alaa Talhami, Avi Swed, Shmuel Hess, Oded Ovadia, Sarit Greenberg, Adi Schumacher-Klinger, David Rosenthal, Deborah E. Shalev, Mattan Hurevich, Philip Lazarovici, Amnon Hoffman, and Chaim Gilon. 2020. “Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.” Frontiers in Chemistry, 8, 1030. Abstract

Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6), which is metabolically stable and has the potential to become a peripheral painkiller being a full μ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6), we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6).

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Multiphosphorylated peptides: importance, synthetic strategies, and applications for studying biological mechanisms
M. Samarasimhareddy, G. Mayer, M. Hurevich, and A. Friedler. 2020. “Multiphosphorylated peptides: importance, synthetic strategies, and applications for studying biological mechanisms.” Org Biomol Chem, 18, 18, Pp. 3405-3422. Abstract

 

Unraveling the role of post-translational modification (PTM) patterns is one of the most urgent and unresolved issues facing the scientific community. Attempts to crack the phosphorylation bio-barcode led to significant findings, which suggest that many proteins cannot be regarded as a single entity but exist as several forms which differ in their phosphorylation patterns and their functions. While protein regions that do not contain PTMs can be rather simply mimicked using peptide libraries, heavily phosphorylated regions are much harder to study using the same tools. The differences between the syntheses of simple mono-, di- and tri-phosphopeptides and the synthesis of multiphosphopeptides are dramatic. While simple phosphopeptides can be synthesized using almost standard SPPS strategies, the synthesis of multiphosphopeptides is to date a major synthetic challenge. Synthesis of multiphosphopeptides requires the insertion of several phosphate groups simultaneously or sequentially into various positions on the peptide in the presence of many other potential modification sites. These groups are bulky, unstable and cannot be easily introduced when in close proximity. Moreover, since the same protein region can possess many alternative multiphosphorylation patterns, libraries comprising a large number of peptides with different degrees and positions of phosphorylation are essential. Many strategies have been developed to provide routes to enable the preparation of multiphosphopeptides. These methods are essentially different from the methods used for the preparation of simple phosphopeptides. In this review, we specifically emphasize the challenges and importance of synthesizing multiphosphopeptides and their libraries. The historical perspective and state of the art strategies are described. We demonstrate here how the different synthetic approaches attempt to address the special problems associated with the synthesis of multiphosphopeptides. The advantages and disadvantages of each strategy are discussed in order to provide a roadmap for the synthesis of such libraries. An overview of the existing strategies and some comments regarding future directions are provided. Applications of multiphosphopeptide libraries as tools to study the effect of phosphorylation patterns on the biological function of proteins are also described.

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A Rapid and Efficient Building Block Approach for Click Cyclization of Peptoids
Mamidi Samarasimhareddy, Mai Shamir, Deborah E. Shalev, Mattan Hurevich, and Assaf Friedler. 2020. “A Rapid and Efficient Building Block Approach for Click Cyclization of Peptoids.” Frontiers in Chemistry, 8, 405. Abstract

Cyclic peptide-peptoid hybrids possess improved stability and selectivity over linear peptides and are thus better drug candidates. However, their synthesis is far from trivial and is usually difficult to automate. Here we describe a new rapid and efficient approach for the synthesis of click-based cyclic peptide-peptoid hybrids. Our methodology is based on a combination between easily synthesized building blocks, automated microwave assisted solid phase synthesis and bioorthogonal click cyclization. We proved the concept of this method using the INS peptide, which we have previously shown to activate the HIV-1 integrase enzyme. This strategy enabled the rapid synthesis and biophysical evaluation of a library of cyclic peptide-peptoid hybrids derived from HIV-1 integrase in high yield and purity. The new cyclic hybrids showed improved biological activity and were significantly more stable than the original linear INS peptide.

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A zinc selective oxytocin based biosensor
E. Mervinetsky, I. Alshanski, K. K. Tadi, A. Dianat, J. Buchwald, R. Gutierrez, G. Cuniberti, M. Hurevich, and S. Yitzchaik. 2020. “A zinc selective oxytocin based biosensor.” J Mater Chem B, 8, 1, Pp. 155-160. Abstract

Oxytocin is a peptide hormone with high affinity to both Zn2+ and Cu2+ ions compared to other metal ions. This affinity makes oxytocin an attractive recognition layer for monitoring the levels of these essential ions in biofluids. Native oxytocin cannot differentiate between Cu2+ and Zn2+ ions and hence it is not useful for sensing Zn2+ in the presence of Cu2+. We elucidated the effect of the terminal amine group of oxytocin on the affinity toward Cu2+ using theoretical calculations. We designed a new Zn2+ selective oxytocin-based biosensor that utilizes the terminal amine for surface anchoring, also preventing the response to Cu2+. The biosensor shows exceptional selectivity and very high sensitivity to Zn2+ in impedimetric biosensing. This study shows for the first time an oxytocin derived sensor that can be used directly for sensing Zn2+ in the presence of Cu2+.

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2019
O. Synhaivska, Y. Mermoud, M. Baghernejad, I. Alshanski, M. Hurevich, S. Yitzchaik, M. Wipf, and M. Calame. 2019. “Detection of Cu(2+) Ions with GGH Peptide Realized with Si-Nanoribbon ISFET.” Sensors (Basel), 19, 18. Abstract

The presence of heavy metal ions such as copper in the human body at certain concentrations and specific conditions can lead to the development of different diseases. The currently available analytical detection methods remain expensive, time-consuming, and often require sample pre-treatment. The development of specific and quantitative, easy-in-operation, and cost-effective devices, capable of monitoring the level of Cu2+ ions in environmental and physiological media, is necessary. We use silicon nanoribbon (SiNR) ion-sensitive field effect transistor (ISFET) devices modified with a Gly–Gly–His peptide for the detection of copper ions in a large concentration range. The specific binding of copper ions causes a conformational change of the ligand, and a deprotonation of secondary amine groups. By performing differential measurements, we gain a deeper insight into the details of the ion–ligand interaction. We highlight in particular the importance of considering non-specific interactions to explain the sensors' response.

 

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Johnny Naoum, Israel Alshanski, Agata Gitlin Domagalska, Moshe Bentolila, Chaim Gilon, and Mattan Hurevich. 2019. “Diffusion Enhanced Amide Bond Formation on Solid Support.” Organic Process Research & Development. Abstract

Mixing of polystyrene resin in solid phase synthesis is performed using shaking or gentle agitation of the reaction vessel to avoid breaking the brittle beads. These mixing strategies result in poor diffusion to and into the beads. Using a large excess of reagents is the common way to compensate for these deficiencies. We used fast overhead stirring for performing coupling reactions on the solid support. We show that fast overhead stirring enhances the efficiency of amide bond formation on solid support compared to the state-of-the-art mixing method while preserving the integrity of the beads. We found that fast over overhead stirring minimizes the effect of decomposition of the activated species by increasing the diffusion dependent coupling reaction. This allows to decrease the excess of reagents used for the multi-step synthesis of peptides, thus, provides greener and more sustainable alternative for peptide synthesis on solid support.

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E. Mervinejsky, I. Alshanski, J. Buchwald, A. Dianat, I. Loncaric, P. Lazic, Z. Crljen, R. Gutierrez, G. Cuniberti, M. Hurevich, and S. Yitzchaik. 2019. “Direct Assembly and Metal-Ion Binding Properties of Oxytocin Monolayer on Gold Surfaces.” Langmuir, 35, 34, Pp. 11114-11122. Abstract

Peptides are very common recognition entities that are usually attached to surfaces using multistep processes. These processes require modification of the native peptides and of the substrates. Using functional groups in native peptides for their assembly on surfaces without affecting their biological activity can facilitate the preparation of biosensors. Herein, we present a simple single-step formation of native oxytocin monolayer on gold surface. These surfaces were characterized by atomic force spectroscopy, spectroscopic ellipsometry, and X-ray photoelectron spectroscopy. We took advantage of the native disulfide bridge of the oxytocin for anchoring the peptide to the Au surface, while preserving the metal-ion binding properties. Self-assembled oxytocin monolayer was used by electrochemical impedance spectroscopy for metal-ion sensing leading to subnanomolar sensitivities for zinc or copper ions.

Langmuir 2019 TOC

D. Mayer, F. F. Damberger, M. Samarasimhareddy, M. Feldmueller, Z. Vuckovic, T. Flock, B. Bauer, E. Mutt, F. Zosel, F. H. T. Allain, J. Standfuss, G. F. X. Schertler, X. Deupi, M. E. Sommer, M. Hurevich, A. Friedler, and D. B. Veprintsev. 2019. “Distinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation.” Nat Commun, 10, 1, Pp. 1261. Abstract

 

The cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Despite high-resolution structural data of arrestins bound to phosphorylated receptor C-termini, the functional role of each phosphorylation site remains obscure. Here, we employed a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determined the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods. We further characterized how these peptides modulated the conformation of arrestin-1 by nuclear magnetic resonance (NMR). Our results indicate that the particular phosphorylation sites can be grouped into different functional classes: ‘key sites’ required for arrestin binding and activation, an ‘inhibitory site’ that abrogates arrestin binding, and ‘modulator sites’ that influence the global conformation of arrestin. These functional motifs allow a better understanding of how different GPCR phosphorylation patterns might control how arrestin functions in the cell.

 

Nat Comm TOC 2019

E. Mervinetsky, I. Alshanski, S. Lenfant, D. Guerin, L. M. Sandonas, A. Dianat, R. Gutierrez, G. Cuniberti, M. Hurevich, S. Yitzchaik, and D. Vuillaume. 2019. “Electron Transport through Self-Assembled Monolayers of Tripeptides.” Journal of Physical Chemistry C, 123, 14, Pp. 9600-9608. Abstract

We report how the electron transport through a solid-state metal/Gly-Gly-His (GGH) tripeptide monolayer/metal junction and the metal/GGH work function (WF) are modified by the GGH complexation with Cu2+ ions. Conducting atomic force microscopy is used to measure the current–voltage histograms. The WF is characterized by combining macroscopic Kelvin probe and Kelvin probe force microscopy at the nanoscale. We observe that the complexation of Cu2+ ions with the GGH monolayer is highly dependent on the molecular surface density and results in opposite trends. In the case of a high-density monolayer the conformational changes are hindered by the proximity of the neighboring peptides, hence forming an insulating layer in response to copper complexation. However, the monolayers of a slightly lower density allow for the conformational change to a looped peptide wrapping the Cu-ion, which results in a more conductive monolayer. Copper-ion complexation to the high- and low-density monolayers systematically induces an increase of the WFs. Copper-ion complexation to the low-density monolayer induces an increase of electron-transport efficiency, whereas the copper-ion complexation to the high-density monolayer results in a slight decrease of electron transport. Both of the observed trends agree with first-principle calculations. Complexation of copper to the low-density GGH monolayer induces a new gap state slightly above the Au Fermi energy that is absent in the high-density monolayer.

JPCC 2019 TOC

I. Alshanski, J. Blaszkiewicz, E. Mervinetsky, J. Rademann, S. Yitzchaik, and M. Hurevich. 2019. “Sulfation Patterns of Saccharides and Heavy Metal Ion Binding.” Chemistry, 25, 52, Pp. 12083-12090. Abstract

Sulfated saccharides are an essential part of extracellular matrices, and they are involved in a large number of interactions. Sulfated saccharide matrices in organisms accumulate heavy metal ions in addition to other essential metal ions. Accumulation of heavy metal ions alters the function of the organisms and cells, resulting in severe and irreversible damage. The effect of the sulfation pattern of saccharides on heavy metal binding preferences is enigmatic because the accessibility to structurally defined sulfated saccharides is limited and because standard analytical techniques cannot be used to quantify these interactions. We developed a new strategy that combines enzymatic and chemical synthesis with surface chemistry and label‐free electrochemical sensing to study the interactions between well‐defined sulfated saccharides and heavy metal ions. By using these tools we showed that the sulfation pattern of hyaluronic acid governs their heavy metal ions binding preferences.

Chem EUJ 2019 TOC

Mamidi Samarasimhareddy, Daniel Mayer, Norman Metanis, Dmitry Veprintsev, Mattan Hurevich, and Assaf Friedler. 2019. “A targeted approach for the synthesis of multi-phosphorylated peptides: a tool for studying the role of phosphorylation patterns in proteins.” Organic & Biomolecular Chemistry, 17, 42, Pp. 9284 - 9290. Abstract

Protein phosphorylation barcodes, clusters of several phosphorylation sites within a short unfolded region, control many cellular processes. Existing biochemical methods used to study the roles of these barcodes suffer from low selectivity and provide only qualitative data. Chemically synthesized multiphosphopeptide libraries are selective and specific, but their synthesis is extremely difficult using the current peptide synthesis methods. Here we describe a new microwave assisted approach for synthesizing a library of multiphosphopeptides, using the C-terminus of rhodopsin as a proof of concept. Our approach utilizes multiple protocols for synthesizing libraries of multiphosphopeptides instead of the inefficient single protocol methods currently used. Using our approach we demonstrated the synthesis with up to seven phosphorylated amino acids, sometimes next to each other, an accomplishment that was impractical before. Synthesizing the Rhodopsin derived multiphosphopeptide library enabled dissecting the precise phosphorylation barcode required for the recruitment, activation and modulation of the conformation of Arrestin. Since phosphorylation barcodes modulate the activity of hundreds of GPCRs, synthesizing libraries of multiphosphopeptides is the method of choice for studying their molecular mechanisms of action. Our approach provides an invaluable tool for evaluating how protein phosphorylation barcodes regulate their activity.

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