Well-defined protein-polymer conjugates—synthesis and potential applications

During the last decades, numerous studies have focused on combining the unique catalytic/functional properties and structural characteristics of proteins and enzymes with those of synthetic molecules and macromolecules. The aim of such multidisciplinary studies is to improve the properties of the natural component, combine them with those of the synthetic, and create novel biomaterials in the nanometer scale. The specific coupling of polymers onto the protein structures has proved to be one of the most straightforward and applicable approaches in that sense. In this article, we focus on the synthetic pathways that have or can be utilized to specifically couple proteins to polymers. The different categories of well-defined protein-polymer conjugates and the effect of the polymer on the protein function are discussed. Studies have shown that the specific conjugation of a synthetic polymer to a protein conveys its physico-chemical properties and, therefore, modifies the biodistribution and solubility of the protein, making it in certain cases soluble and active in organic solvents. An overview of the applications derived from such bioconjugates in the pharmaceutical industry, biocatalysis, and supramolecular nanobiotechnology is presented at the final part of the articl

Face-selectivity in [4+2]-cycloadditions to novel polycyclic benzoquinones. Remarkable stereodirecting effects of a remote cyclopropane ring and an olefinic bond

π-Face selectivity in Diels-Alder reactions between specially crafted bicyclo[2.2.2]octane-fused benzoquinones, where the dienophilic moiety is imbedded in an isosteric environment, can be modulated by a remote olefinic bond and a cyclopropane ring. Quantum mechanical calculations while reproducing the observed diastereoselectivities at the TS level indicate the involvement of ground state orbital effects

Simultaneous control of emission localization and two-photon absorption efficiency in dissymmetrical chromophores

C. K's secondary address for this work: CNRS UMR6082 FOTON, INSA de Rennes, 20 avenue des Buttes de Coësmes, CS 70839, 35708 RENNES cedex 7, FranceWe thank E. Leroux for technical assistance in the synthesis, S. Soualmi in electrochemical mesaurements and M. H. V. Werts for help in the TPEF measurements.International audienceThe aim of the present work is to demonstrate that combined spatial tuning of fluorescence and two-photon absorption (TPA) properties of multipolar chromophores can be achieved by introduction of slight electronic chemical dissymmetry. In that perspective, two model series of structurally related chromophores have been designed and investigated. One is based on rod-like quadrupolar chromophores bearing either two identical or different electron-donating (D) end groups and the other on three-branched octupolar chromophores built from a trigonal donating moiety bearing identical or different acceptor (A) peripheral groups. The influence of the electronic dissymmetry is investigated by combined experimental and theoretical studies of the linear and nonlinear optical properties of dissymmetrical chromophores compared to their symmetrical counterparts. In both types of systems (i.e., quadrupoles and octupoles), experiments and theory reveal that excitation is essentially delocalized and that excitation involves synchronized charge redistribution (i.e., concerted intramolecular charge transfer) between the different D and A moieties within the multipolar structure. In contrast, the emission stems only from a particular dipolar subunit bearing the strongest D or A moiety due to fast excitation localization after excitation, prior to emission. Hence, control of emission characteristics (polarization and emission spectrum), can be achieved, in addition to localization, by controlled introduction of electronic dissymmetry (i.e., replacement of one of the D or A end-groups by a slightly stronger D′ or A′ unit). Interestingly, slight dissymmetrical functionalization of both quadrupolar and octupolar compounds does not lead to significant loss in TPA responses and can even be beneficial due to the spectral broadening and peak position tuning that it allows. This study thus reveals an original molecular engineering route allowing TPA enhancement in multipolar structures, due to concerted core-to-periphery or periphery-to-core intramolecular charge redistribution upon excitation, while providing for control of emission localization. Such a route could be extended to more intricate (dendritic) and multipolar (3D) systems

Preparation of silk fibroin–poly(ethylene glycol) conjugate films through click chemistry

Azide silk fibroin (azido SF) and alkyne terminal poly(ethylene glycol) (PEG) 2000 (acetylene-terminal PEG 2000) were synthesized. Azido SF was reacted with acetylene-terminal PEG 2000 to produce films via a copper-mediated 1,3-cycloaddition (‘click’ chemistry) generating a triazole linkage as the networking forming reaction. Through click chemistry, novel silk-based films with various weight ratios were prepared and investigated. Fourier transform infrared, X-ray diffraction and differential scanning calorimetry analyses showed that the ordered association of the PEG molecules is strongly constrained by the presence of the SF molecules and crosslinking and that the presence of acetylene-terminal PEG 2000 in the films induced crystallization to a β-sheet of SF chains.Water content and contact angle measurements indicated that the hydrophilicity of the films increased compared with SF. SF–PEG films exhibited smooth and rough structures, depending on degree of crosslinking and on the weight ratio of SF and PEG, as shown by scanning electron microscopy

An appraisal of the Suzuki cross-coupling reaction for the synthesis of novel fluorescent coumarin derivatives

We report the chemical design and development of 3-aryl-substituted 7-alkoxy-4-methylcoumarins with enhanced fluorogenic properties. The 3-aryl substituents are installed via an optimized Suzuki–Miyaura cross-coupling (SMC) reaction between a 7-alkoxy-3-bromo-4-methylcoumarin and aryl boronic MIDA esters using Pd(OAc)2/XPhos in a catalytic system with K2CO3 in aqueous THF. Under these conditions, an exocyclic ester functionality is found to be unaffected. Subsequent saponification revealed a carboxylic acid functionality that is suitable for conjugation reactions. Evaluation of their fluorescence properties indicated that the installed 3-heteroaryl substituent, particularly benzofuran-2-yl, resulted in a significant red shift of both the excitation and emission wavelengths

Ruthenium-Catalyzed Azide–Thioalkyne Cycloadditions in Aqueous Media: A Mild, Orthogonal, and Biocompatible Chemical Ligation

The development of efficient metal-promoted bioorthogonal ligations remains as a major scientific challenge. Demonstrated herein is that azides undergo efficient and regioselective room-temperature annulations with thioalkynes in aqueous milieu when treated with catalytic amounts of a suitable ruthenium complex. The reaction is compatible with different biomolecules, and can be carried out in complex aqueous mixtures such as phosphate buffered saline, cell lysates, fetal bovine serum, and even living bacteria (E. coli). Importantly, the reaction is mutually compatible with the classical CuAACThis work has received financial support from Spanish grants (SAF2016-76689-R and SAF2013-41943-R), the Xunta de Galicia (2015-CP082 and Centro Singular de Investigaciln de Galicia accreditation 2016-2019 ED431G/09), the European Union (European Regional Development Fund - ERDF), and the ERC (Adv. Grant 340055)S

In situ conjugation of dithiophenol maleimide polymers and oxytocin for stable and reversible polymer–peptide conjugates

The in situ one-pot synthesis of peptide–polymer bioconjugates is reported. Conjugation occurs efficiently without the need for purification of dithiophenol maleimide functionalized polymer as a disulfide bridging agent for the therapeutic oxytocin. Conjugation of polymers was demonstrated to be reversible and to significantly improve the solution stability of oxytocin

Genetic landscape of a large cohort of Primary Ovarian Insufficiency : New genes and pathways and implications for personalized medicine

Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield-ing infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology.Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromo-somal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link.Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogene-sis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.Funding Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe