New Article in Angewandte Chemie
Henry W. Orton, Jan Stanek, Tobias Schubeis, Dylan Foucaudeau, Claire Ollier, Adrian W. Draney, Tanguy Le Marchand, Diane Cala-De Paepe, Isabella C. Felli, Roberta Pierattelli, Sebastian Hiller, Wolfgang Bermel, Guido Pintacuda
Narrow proton signals, high sensitivity, and efficient coherence transfersprovided by fast magic-angle spinning at high magnetic fields make automated projection spectroscopy feasible in protein solid-state NMR. We present the first ultra-high dimensional implementation of this approach where 5D peak lists are reconstructed from a number of 2D projections for protein samples of different molecular size and aggregation state, featuring limited dispersion of chemical shifts or inhomogeneous broadenings. The resulting datasets are particularly suitable to automated analysis, yielding rapid and unbiased backbone resonance assignments.
New Article in ACS Medicinal Chemistry Letters
Azzurra Stefanucci, Wei Lei, Stefano Pieretti, Marilisa Pia Dimmito, Grazia Luisi, Ettore Novellino, Michał Nowakowski, Wiktor Koźmiński, Sako Mirzaie, Gokhan Zengin, John M. Streicher, and Adriano Mollica
In this work we report the application of the ring-closing metathesis (RCM) to the preparation of two cyclic olefin-bridged analogues of biphalin (Tyr-d-Ala-Gly-Phe-NH-NH ← Phe ← Gly ← d-Ala ← Tyr), using the second generation Grubbs’ catalyst. The resulting cis- and trans-cyclic isomers were identified, fully characterized, and tested in vitro at μ (ΜΟR), δ (DOR), and κ (KOR) opioid receptors and in vivo for antinociceptive activity. Both were shown to be full agonists at MOR and potential partial antagonists at DOR, with low potency KOR agonism. They also share a strong antinociceptive effect after intracerebroventricular (i.c.v.) and intravenous (i.v.) administration, higher than that of the cyclic biphalin analogues containing a disulfide bridge between the side chains of two d-Cys or d-Pen residues, previously described by our group.
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New Review in Journal of Inorganic Biochemistry
Samah Al-Harthi, Joanna Lachowicz, Michał Nowakowski, Mariusz Jaremko, Łukasz Jaremko
Human serum albumin (HSA) is a monomeric, globular, multi-carrier and the most abundant protein in the blood. HSA displays multiple ligand binding sites with extraordinary binding capacity for a wide range of ions and molecules. For decades, HSA's ability to bind to various ligands has led many scientists to study its physiological properties and protein structure; indeed, a better understanding of HSA-ligand interactions in human blood, at the atomic level, will likely foster the development of more potent, and overall more performant, diagnostic and therapeutic tools against serious human disorders such as diabetes, cardiovascular disorders, and cancer. Here, we present a concise overview of the current knowledge of HSA's structural characteristics, and its coordination chemistry with transition metal ions, within the scope and limitations of current techniques and biophysical methods to reach atomic resolution in solution and in blood serum. We also highlight the overwhelming need of a detailed atomistic understanding of HSA dynamic structures and interactions that are transient, weak, multi-site and multi-step, and allosterically affected by each other. Considering the fact that HSA is a current clinical tool for drug delivery systems and a potential contender as molecular cargo and nano-vehicle used in biophysical, clinical and industrial fields, we underline the emerging need for novel approaches to target the dynamic functional coordination chemistry of the human blood serum albumin in solution, at the atomic level.
New Article in Physical Chemistry Chemical Physics
Jacek Wójcik, Andrzej Ejchart, Michał Nowakowski
Complex formation between quinine and natural cyclodextrins (CD) was studied using NMR spectroscopy. The strongest association was observed for complexes of neutral quinine molecule with βCD. Association constants for monokationic quinine were one order of magnitude smaller, while dikationic quinine did not bind to CDs. Distribution of complexation-induced shifts and ROESY spectra revealed bimodal quinine binding in complexes built up by βCD and γCD. Complex formation resulted in decrease of vicinal coupling constant between H2 and H9 protons owing to the rotation about C2–C9 bond and in consequence in mutual reorientation of two main constituents of quinine: quinoline and quinuclidine. DFT calculations allowed to establish that H2 and H9 protons are antiperiplanar in the prevailing quinine conformer(s) in aqueous solution. Conformers with synclinal H2, H9 protons become to participate in quinine complexed with CDs.
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