Exploring the Chemical Properties and Medicinal Applications of Tetramethylthiocycloheptyne Sulfoximine Used in Strain-Promoted Azide-Alkyne Cycloaddition Reactions.

The recently developed compound, tetramethylthiocycloheptyne sulfoximine (TMTHSI), has shown to be a promising strained alkyne for strain-promoted azide-alkyne cycloaddition (SPAAC), metal-free click chemistry. This research explores the properties of TMTHSI-based compounds via three aspects: (1) large-scale production, (2) unique stability in acidic conditions and its subsequent use in peptide synthesis, and (3) the functionalization of antibodies. Here, it is shown that (1) scale-up is achieved on a scale of up to 100 g.

Click Bioconjugation: Modifying Proteins Using Click-Like Chemistry.

Bioconjugation deals with the chemical modification of proteins. The reactions used exploit either the intrinsic chemical reactivity of the biomolecule or introduce functionalities that can then be subsequently reacted without interfering with other functional groups of the biological entity. Perfectly selective, high yielding chemical transformations are needed that can be run in aqueous environment under mild pH conditions.

Conjugation process development and scale-up.

Manufacturing highly potent antibody-drug conjugates (ADCs) is a demanding task-combining conventional organic synthesis with biotechnological manufacturing. Hence a series of new and unique engineering and chemistry challenges have to be addressed to support clinical trials and commercial manufacturing. These include the development of reliable processes leading to uniform product properties, as well as establishment of ADC-specific analytical methods and safe strategies for handling cytotoxic compounds.

Safe handling of cytotoxic compounds in a biopharmaceutical environment.

Handling cytotoxic drugs such as antibody-drug conjugates (ADCs) in a biopharmaceutical environment represents a challenge based on the potency of the compounds. These derivatives are dangerous to humans if they accidentally get in contact with the skin, are inhaled, or are ingested, either as pure compounds in their solid state or as a solution dissolved in a co-solvent. Any contamination of people involved in the manufacturing process has to be avoided.

Generation of candidate ligands for nicotinic acetylcholine receptors via in situ click chemistry with a soluble acetylcholine binding protein template.

Nicotinic acetylcholine receptors (nAChRs), which are responsible for mediating key physiological functions, are ubiquitous in the central and peripheral nervous systems. As members of the Cys loop ligand-gated ion channel family, neuronal nAChRs are pentameric, composed of various permutations of α (α2 to α10) and β (β2 to β4) subunits forming functional heteromeric or homomeric receptors. Diversity in nAChR subunit composition complicates the development of selective ligands for specific subtypes, since the five binding sites reside at the subunit interfaces.

Synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds.

Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site.

Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies.

Antibody-drug conjugates (ADCs) combine the specificity of monoclonal antibodies (mAbs) with the potency of cytotoxic molecules, thereby taking advantage of the best characteristics of both components. Along with the development of the mAbs and cytotoxins, the design of chemical linkers to covalently bind these building blocks is making rapid progress but remains challenging. Recent advances have resulted in linkers having increased stability in the bloodstream while allowing efficient payload release within the tumor cell.

Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities.

Trypanothione reductase (TR) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against African sleeping sickness and Chagas' disease. Diaryl sulfides with a central anilino moiety, decorated with a flexible N-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. Using computer modelling, we revised the binding model for this class of TR inhibitors predicting simultaneous interactions of the ammonium ion-terminated N-alkyl chain with Glu18 as well as Glu465'/Glu466' of the second subunit of the homodimer, whereas the hydrophobic substituent of the aniline ring occupies the "mepacrine binding site" near Trp21 and Met113.