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Flow Chemistry Highlights: Selected Topic: An Interview with Ben Martin from Novartis, Basel
No full textHow to Accelerate R&D and Optimize Experiment Planning with Machine Learning and Data Science
Get PDFAccelerating R&D is essential to address some of the challenges humanity is currently facing, such as achieving the global sustainability goals. Today’s Edisonian approach of trial-and-error still prevalent in R&D labs takes up to two decades of fundamental and applied research for new materials to reach the market. Turning around this situation calls for strategies to upgrade R&D and expedite innovation. By conducting smart experiment planning that is data-driven and guided by AI/ML, researchers can more efficiently search through the complex - often constrained - space of possible experiments and find or hit the global optima much faster than with the current approaches. Moreover, with digitized data management, researchers will be able to maximize the utility of their data in the short and long terms with the aid of statistics, ML and visualization tools. In what follows, we describe a framework and lay out the key technologies to accelerate R&D and optimize experiment plannin
Flow chemistry Set-up Enables Integration of Chemo- and Biocatalysis
Get PDFThe move towards sustainable syntheses is a widespread effort which sees academia and industry developing new strategies and solutions. Flow chemistry, and in general the flow set up, with the compartmentalization of different steps in dedicated reactors, offers new possibility to integrate biocatalytic steps within a chemical cascade, often without the need to redesign the whole pathway. Here we report key examples in the field over the past few years
How to Find Molecules with Long-lasting Charge Migration?
Get PDFUnder certain conditions, the ionization of a molecule may create a superposition of electronic states, leading to ultrafast electron dynamics. If controlled, this motion could be used in attochemistry applications, but it has been shown that the decoherence induced by the nuclear motion typically happens in just a few femtoseconds. We recently developed an efficient algorithm for finding molecules exhibiting long-lasting electronic coherence and charge migration across the molecular structure after valence ionization. Here, we first explain why the but-3-ynal molecule is a promising candidate to study this type of ultrafast electron dynamics. Then, we use the 3-oxopropanenitrile molecule, which does not induce long-lasting charge migration in any of three different ionization scenarios, as an example demonstrating that several different properties must be fulfilled simultaneously to make the attochemistry applications possible
Late Microaerobic Growth for Efficient Production of Human Cytochrome P450 3A4 in E. coli
Get PDFDetailed preclinical characterization of metabolites formed in vivo from candidate drug substances is mandatory prior to the initiation of clinical trials. Therefore, inexpensive and efficient methods for drug metabolite synthesis are of high importance for rapid advancement of the drug development process. A large fraction of small molecule drugs is modified by monooxygenase cytochrome P450 3A4 produced in the human liver and intestine. Therefore, this enzyme is frequently employed to catalyze metabolite synthesis in vitro, making 3A4 availability a critical requirement in early drug development. Unfortunately, the recombinant production of this enzyme in microbial hosts is notoriously difficult. Maintaining low oxygen transfer rates and the use of rich media for host cultivation are required for P450 3A4 production. However, detailed studies on the relationship between oxygen supply and P450 3A4 space-time yields are missing. We describe an improved biotechnological process for the heterologous expression of P450 3A4 together with its redox partner, cytochrome P450 reductase, in Escherichia coli. Enzyme production was most efficient under so-called “late microaerobic” growth conditions, in which the cells have just not yet made the switch to anaerobic metabolism, characterized by a limited oxygen supply leading to oxygen concentrations in the liquid phase that are far below the detection limit of standard oxygen electrodes. Furthermore, feeding the carbon source glycerol as well as controlling cellular acetate formation improved process productivity. The presented protocol resulted in the formation of functional recombinant 3A4 at concentrations up to 680 nmol L-1
Advances in Noncanonical Amino Acid Incorporation for Enzyme Engineering Applications
Get PDFIncorporation of noncanonical amino acids (ncAAs) via genetic code expansion (GCE) opens up new possibilities for chemical biology. The technology has led to the development of novel xenobiotic enzymes with tailored properties which can serve as entry points into a multitude of applications, including protein conjugation, immobilization, or labeling. In this review, we discuss recent progress in the use of GCE to create biocatalysts possessing reaction repertoires that lie beyond what is achievable with canonical amino acids (cAAs). Furthermore, we highlight how GCE enables to gain mechanistic insights into protein function by the incorporation of judiciously selected ncAAs. As the amino acid alphabet continues to grow and improved tools for ncAA incorporation are being developed, we anticipate the creation of additional powerful biological catalysts for synthetic application which merge the chemical versatility of anthropogenic building blocks with the exquisite selectivities of enzymes
Repurposing of Tuberculosis Drug Candidates for the Treatment of Mycobacterium ulcerans Disease
Get PDFBuruli ulcer (BU) is a chronic necrotizing skin disease caused by Mycobacterium ulcerans. Historically, the disease was treated by surgical excision of the skin lesions, until an 8-week combination therapy of rifampicin and streptomycin was introduced in 2004. This treatment modality was effective and reduced recurrence rates. Rifampicin is the most efficacious antibiotic for the treatment of BU and, should rifampicin-resistant M. ulcerans strains emerge, there is currently no replacement for it. As for mycobacterial diseases in general, there is a pressing need for the development of novel, fast-acting drugs. Under market economy conditions, repurposing of new tuberculosis drug candidates is the most promising avenue for alternative BU treatments. Our drug repurposing activities have led to the identification of several actives against M. ulcerans. In particular, the cytochrome bc1 complex inhibitor telacebec (Q203) is a promising drug candidate for the treatment of BU in Africa and Australia. While an active cytochrome-bd oxidase bypass limits the potency of the cytochrome-bc1-specific inhibitor telacebec against M. tuberculosis, classical lineage M. ulcerans strains rely exclusively on cytochrome-bc1 to respire. Hence, telacebec is effective at nanomolar concentration against M. ulcerans, and a high treatment efficacy in an experimental mouse infection model indicates that treatment of BU could be substantially shortened and simplified by telacebec
