Biocompatible and selective generation of bicyclic peptides

Ullrich, Sven; George, Josemon; Coram, Alexandra; Morewood, Richard; Nitsche, Christoph

doi:10.26434/chemrxiv-2022-xw6cm

Cited by 2 publications

(2 citation statements)

References 10 publications

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“…FDCP was synthesized from commercially available 4-chloro-2,6-dicyanopyridine (Ambeed, USA) in a single step by heating with CsF as reported elsewhere (Ullrich et al, 2022). The Supporting Information provides the detailed protocol for the synthesis of (S)-3-amino-4-mercaptobutanoic acid (b-cysteine).…”

Section: Synthesis Of 4-fluoro-26-dicyanopyridine (Fdcp) and B-cysteinementioning

confidence: 99%

Site-selective generation of lanthanoid binding sites on proteins using 4-fluoro-2,6-dicyanopyridine

Tharayil

Mahawaththa

Feintuch

et al. 2022

Preprint

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Abstract. The paramagnetism of a lanthanoid tag site-specifically installed on a protein provides a rich source of structural information accessible by nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy. Here we report a lanthanoid tag that reacts selectively with cysteine or selenocysteine with formation of a (seleno)thioether bond and a short tether between lanthanoid ion and protein backbone. The tag is assembled on the protein in three steps, comprising (i) reaction with 4-fluoro-2,6-dicyanopyridine (FDCP), (ii) reaction of the cyano groups with α-cysteine, penicillamine or β-cysteine to complete the lanthanide chelating moiety and (iii) titration with a lanthanoid ion. FDCP reacts much faster with selenocysteine than cysteine, opening a route for selective tagging in the presence of solvent-exposed cysteine residues. Loaded with Tb3+ and Tm3+ ions, pseudocontact shifts were observed in protein NMR spectra, confirming that the tag delivers good immobilisation of the lanthanoid ion relative to the protein, which was also manifested in residual dipolar couplings. Completion of the tag with different 1,2-amino thiol compounds resulted in different magnetic susceptibility tensors. In addition, the tag proved suitable for measuring distance distributions in double electron–electron resonance experiments after titration with Gd3+ ions.

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Section: Synthesis Of 4-fluoro-26-dicyanopyridine (Fdcp) and B-cysteinementioning

confidence: 99%

Site-selective generation of lanthanoid binding sites on proteins using 4-fluoro-2,6-dicyanopyridine

Tharayil

Mahawaththa

Feintuch

et al. 2022

Preprint

Self Cite

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“…According to the molecular simulation and mass spectroscopy, carbonyl group of Carmofur covalently binds to the essential catalytic amino acid residue Cys145. Different from N3 which occupies four subsites S1, S2, S4 and S1, [11,12] the crystal structure of SARS‐CoV‐2 M pro revealed the transfer of the hexylurea side chain from Carmofur to Cys145 in M pro , the fatty acid tail of the drug as a residual hexylcarbamothioate appears to interact with His41 and other existing residues into the hydrophobic S2 subsite in the binding pocket of this cysteine protease (PDB: 7BUY).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and In Silico Investigation of Isatin‐Based Schiff Bases as Potential Inhibitors for Promising Targets against SARS‐CoV‐2

et al. 2022

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Despite the significant development in vaccines and therapeutics cocktails, there is no specific treatment available for coronavirus disease 2019 (COVID‐19), caused by the new severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Targeting the main protease (Mpro) of SARS‐CoV‐2, which possesses a key role in producing the essential viral structural and functional proteins, can be considered an efficient way to control this potentially lethal infection. Recently, some of Michael acceptor‐pharmacophore containing inhibitors have been suggested as successful suppressors of the main protease. Here, we synthesized the Isatin‐based Schiff bases possessing the structural pattern of a Michael acceptor‐like portion employing synthesis procedures. In silico investigation of these compounds was not limited to the main protease. We have also evaluated their possible inhibitory activity against the other identified druggable targets using homology modeling, molecular docking, and molecular dynamics simulations. Our investigations revealed that the dimethyl biguanide carrying Schiff bases of Isatin‐derivatives have the best binding mode and interaction energy. The dimethyl biguanide moiety‐containing compounds have formed promising interactions with the key amino acid residues Cys145 and HIS41 of Mpro with a binding free energy of −7.6 kcal/mol which was lower than the positive control compound Carmofur (−6.3 kcal/mol). It also leads to the higher affinity and the much inhibitory potential against the SARS‐CoV‐2 RdRp and Spike glycoproteins, human TMPRSS2, and ACE2 receptors.

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Biocompatible and selective generation of bicyclic peptides

Cited by 2 publications

References 10 publications

Site-selective generation of lanthanoid binding sites on proteins using 4-fluoro-2,6-dicyanopyridine

Site-selective generation of lanthanoid binding sites on proteins using 4-fluoro-2,6-dicyanopyridine

Synthesis and In Silico Investigation of Isatin‐Based Schiff Bases as Potential Inhibitors for Promising Targets against SARS‐CoV‐2

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