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Chemical tools and methods that report on G protein-coupled receptor (GPCR) expression levels and receptor occupancy by small molecules are highly desirable. We report the development of LEI121 as a photoreactive probe to study the type 2 cannabinoid receptor (CB2R), a promising GPCR to treat tissue injury and inflammatory diseases. LEI121 is the first CB2R-selective bifunctional probe that covalently captures CB2R upon photoactivation. An incorporated alkyne serves as ligation handle for the introduction of reporter groups. LEI121 enables target engagement studies and visualization of endogenously expressed CB2R in HL-60 as well as primary human immune cells using flow cytometry. Our findings show that strategically functionalized probes allow monitoring of endogenous GPCR expression and engagement in human cells using tandem photoclick chemistry and hold promise as biomarkers in translational drug discovery.

Proteins with a functionalized C-terminus such as a C-terminal thioester are key to the synthesis of larger proteins via expressed protein ligation. They are usually made by recombinant fusion to intein. Although powerful, the intein fusion approach suffe

Two cases of spontaneous evolution of monomers to linear polymers having novel cross-laminated topology are reported. We synthesized two peptide monomers N3-Gly-Gly-NH-CH2-CCH and N3-Gly-Gly-Gly-CH2-CCH and solved their crystal structures by single-crystal X-ray diffraction. They adopt H-bonded crisscrossed layered packing in their crystals such that: (a) the monomers are aligned head-to-tail in 1D-chain-like arrays and parallel arrangement of such arrays forms a layer; (b) the proximally placed azide and alkyne motifs are in an orientation apt for their regiospecific cycloaddition; (c) each monomer having x peptide bonds is H-bonded with 2x monomers disposed in intersecting arrangement, which pre-organize 1D-chain-like arrays in adjacent layers in perpendicular orientation. These crystals underwent spontaneous single-crystal-to-single-crystal (SCSC) polymerization via azide–alkyne cycloaddition reaction to form triazolyl-polyglycines, at room temperature. The crisscrossed arrangement of monomers in adjacent layers ensured the formation of cross-laminated polymers.

Mercaptobenzamide thioesters and thioethers are chemically simple HIV-1 maturation inhibitors with a unique mechanism of action, low toxicity, and a high barrier to viral resistance. A structure-activity relationship (SAR) profile based on 39 mercaptobenzamide prodrug analogs exposed divergent activity/toxicity roles for the internal and terminal amides. To probe the relationship between antiviral activity and toxicity, we generated an improved computational model for the binding of mercaptobenzamide thioesters (SAMTs) to the HIV-1 NCp7 C-terminal zinc finger, revealing the presence of a second low-energy binding orientation, hitherto undisclosed. Finally, using NMR-derived thiol–thioester exchange equilibrium constants, we propose that thermodynamics plays a role in determining the antiviral activity observed in the SAR profile.

A copper(I)-mediated denitrogenative reaction has been successfully developed for the preparation of cyclic tetrapeptides. The key reactive intermediate, ketenimine, triggers intramolecular cyclization through attack of the terminal amine group to generate an internal β-amino acid with an amidine linkage. The chemistry developed herein provides a new synthetic route for the preparation of cyclic α3β-tetrapeptide analogues that contain important biological properties and results in rich structural information being obtained for conformational studies. With the success of this copper(I)-catalyzed macrocyclization, two histone deacetylase inhibitor analogues consisting of the cyclic α3β-tetrapeptide framework have been successfully synthesized.

The present invention provides a dihydroisoxazole of formula: or a salt thereof, for use in the control of sea lice in fish.

Described herein are compounds and compositions that modulate the activity of beta -lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.

Alkyl esters, such as propargyl esters, typically lack the electron-withdrawing inductive effects needed to participate in nucleophilic acyl substitution reactions. Herein, we report an unusual observation in which glycine propargyl ester derivatives displayed selective, base-independent reactivity towards linear alkylamines under mild, metal-free conditions. Through global reaction route mapping (GRRM) modeling calculations, it is predicted that these observations may be governed by factors related to hydrogen-bonding and intermolecular interactions, rather than electron-withdrawing inductive effects. Based on this concept of propargyl-assisted selective amidation, a direct application was made to develop a novel site-specific C-terminal glycine peptide bioconjugation technique as a proof-of-concept, which relies upon the selective reactivity of glycine propargyl esters over that of aspartate and glutamate side-chain-linked propargyl esters.

The present invention concerns compounds of formula (I) or an N-oxide or salt thereof and their use for controlling parasites in and on warm-blooded animals or fish.

We report the design, synthesis and antibacterial activity analysis of conjugates of vancomycin and cathelicidin-related antimicrobial peptides (CRAMP). Vancomycin inhibits the nascent peptidoglycan synthesis and is highly active against Gram-positive bacteria, whereas Gram-negative bacteria are generally insensitive due to a protective outer membrane. CRAMP is known to translocate across the Gram-negative outer membrane by a self-promoted uptake mechanism. Vancomycin-CRAMP conjugates were synthesized using click chemistry with diverse hydrophilic and hydrophobic linkers, with CRAMP functioning as a carrier peptide for the transfer of vancomycin through the outer membrane. Small hydrophobic linkers with an aromatic group result in the most active conjugates against planktonic Gram-negative bacteria, while maintaining the high activity of vancomycin against Gram-positive bacteria. These conjugates thus show a broad-spectrum activity, which is absent in CRAMP or vancomycin alone, and which is strongly improved compared to an equimolar mixture of CRAMP and vancomycin. In addition, these conjugates also show a strong inhibitory activity against S. Typhimurium biofilm formation.

We report the design, synthesis and antibacterial activity analysis of conjugates of vancomycin and cathelicidin-related antimicrobial peptides (CRAMP). Vancomycin inhibits the nascent peptidoglycan synthesis and is highly active against Gram-positive bacteria, whereas Gram-negative bacteria are generally insensitive due to a protective outer membrane. CRAMP is known to translocate across the Gram-negative outer membrane by a self-promoted uptake mechanism. Vancomycin-CRAMP conjugates were synthesized using click chemistry with diverse hydrophilic and hydrophobic linkers, with CRAMP functioning as a carrier peptide for the transfer of vancomycin through the outer membrane. Small hydrophobic linkers with an aromatic group result in the most active conjugates against planktonic Gram-negative bacteria, while maintaining the high activity of vancomycin against Gram-positive bacteria. These conjugates thus show a broad-spectrum activity, which is absent in CRAMP or vancomycin alone, and which is strongly improved compared to an equimolar mixture of CRAMP and vancomycin. In addition, these conjugates also show a strong inhibitory activity against S. Typhimurium biofilm formation.

Antifreeze glycoproteins (AFGPs) are important naturally occurring biological antifreezes that lower the freezing point of a solution, thereby preventing uncontrolled ice growth. These compounds also inhibit ice recrystallization. Described in this paper is a synthetic antifreeze glycopeptide-based polymer synthesized from an azide/alkyne glycopeptide building block by partial reduction of the azide and subsequent copper catalyzed azide alkyne cycloaddition (CuAAC) polymerization to obtain linear oligomers. To compare the activity with native AFGPs, a linear dodecapeptide (oligomer with four repeating units) was synthesized and isolated which had a comparable length to AFGP-8, the lowest molecular mass glycoprotein AFGP found in nature. In terms of ice recrystallization inhibition (IRI) activity, the triazole-based oligomers displayed only modest IRI activity compared with AFGP-8 and a previously described carbon-linked AFGP analogue. However, CD spectroscopy showed that the triazole-based tetramer possessed a similar secondary structure to the related amide based carbon-linked AFGP tetramer based on AFGP-8. This journal is the Partner Organisations 2014.

Two new cyclic RGD peptides were prepared using a click chemistry approach. The linear RGDfV peptide was synthesized by solid-phase peptide synthesis using a 9-fluorenylmetoxicarbonyl (Fmoc) strategy and a 2-chlorotrityl chloride resin. After coupling 5-h

A range of macrocyclic β-turn mimetic tetrapeptides was prepared by efficient copper-tris(triazole) ligand complex catalyzed azide-alkyne "click" macrocyclizations in good to high yields. Preliminary conformational studies using X-ray crystallography and NMR spectroscopy demonstrated the presence of intramolecular H-bonds characteristic of β-turns in these cyclic tetrapeptides.

A new triazole oxotechnetium chelating agent was synthesized via a 'Click-to-Chelate' strategy. In vivo evaluation of the corresponding 99mTc complex shows that the tracer exhibits very interesting properties for molecular imaging.

Bioinspired modular synthesis of elastin-mimic polymers (EMPs) is achieved via Cu-catalyzed alkyne-azide cyclization (CuAAC). By changing the module, EMPs with different secondary structures determined by circular dichroism (CD) spectra in trifluoroethanol (TFE) solution are obtained. The EMPs are characterized by measuring the lower critical solution temperatures (LSCTs) and the bulk mechanic properties under the conditions of both dry and hydrated forms. The unique molecular design enables us to probe mechanistic questions and assess the structure-property relationship of the EMPs. Our results indicate that, instead of a highly organized secondary structure, hydrophobic hydration is critical for the elasticity of EMPs.

The fact that GPCRs might function in a dimeric fashion is currently well accepted. For GnRHR, a GPCR that regulates gonadotropin release, there is evidence that the receptor also functions as a dimer. We here describe the design and synthesis of a set of dimeric GnRHR antagonists in order to understand the interaction of dimeric ligands to the receptor and to address the question whether GnRHR dimerization is a prerequisite for signalling. Biological evaluation of the compounds shows no discrimination between monomeric and dimeric-ligands in respect to binding affinities, however, the dimeric ligands appear to have different functional properties.

Copper-catalyzed azide alkyne cycloadditions of the linear substrates 1 were used to form the cyclic derivatives 2. Computational, NMR, and CD analyses of these compounds indicate that their most favorable conformational states include type I and type II