Current opinion in biotechnology最新文献

Agonists of the cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway, a critical mediator of innate immune response to foreign invaders with DNA, have gained significant interest in cancer immunotherapy. STING agonists are envisioned as a way of complementing the antitumor activity of the patient’s immune system and immune checkpoint blockade therapy. However, their clinical development has been challenging due to the poor pharmacokinetic and physicochemical properties. This review discusses drug delivery efforts to circumvent the challenges, their accomplishment, and unmet needs based on the last five years of literature.

Natural products represent an inestimable source of valuable compounds for human health. Notably, those produced by plants remain challenging to access due to their low production. Potential shortages of plant-derived biopharmaceuticals caused by climate change or pandemics also regularly tense the market trends. Thus, biotechnological alternatives of supply based on synthetic biology have emerged. These innovative strategies mostly rely on the use of engineered microbial systems for compound synthesis. In this regard, yeasts remain the easiest-tractable eukaryotic models and a convenient chassis for reconstructing whole biosynthetic routes for the heterologous production of plant-derived metabolites. Here, we highlight the recent discoveries dedicated to the bioproduction of new-to-nature compounds in yeasts and provide an overview of emerging strategies for optimising bioproduction.

Because of their complicated biosynthesis and hydrophobic nature, fermentative production of terpenoids did not play a significant role on a commercial scale until a few years ago. Driven by technological progress in metabolic engineering and process biotechnology, terpene-based food ingredients such as flavors, sweeteners, and vitamins produced by fermentation have now become viable and commercially competitive options. In recent years, several companies have developed microbial platforms for commercial terpene production. Impressive progress has been made in the fermentative production of sesquiterpenes used in flavorings. The development of sweeteners, such as steviol glycosides and mogrosides, and the production of vitamins A and E based on fermentation are also being explored. The production of monoterpenes remains challenging due to their antimicrobial effects.

Carotenoids are natural pigments that exhibit a wide range of red, orange, and yellow colors and are extensively used in the food, nutraceuticals, cosmetics, and aquaculture industries. While advances in systems metabolic engineering have established a foundation for constructing carotenoid-producing microbial cell factories at a laboratory scale, translating these technologies to industrial scales remains a big challenge. Moreover, there is a need to devise cost-effective methods for downstream processing and purification of carotenoids. In this review, we discuss recent strategies in metabolic engineering, such as metabolic flux optimization, enzyme assembly, and storage capacity engineering, aimed at constructing high-performance carotenoid-producing microbial strains. We also review recent approaches for cost-effective downstream processing and purification of carotenoids.

In this era of pandemics, reducing the risk of lifestyle-related diseases (LRD) by functional foods is of paramount importance. The conventional process of functional food development almost invariably involves in vitro, animal, and human intervention trials, but differences in intestinal environments between humans and experimental animals make it difficult to develop functional foods that are truly effective in humans. Thus, it is necessary to construct a model that simulates the human intestinal environment to evaluate the functionality of any food component before subjecting it to a human intervention trial. In this review, we provide an overview of a model simulating human intestinal microbiota constructed at Kobe University and its use as a tool to identify food components that contribute to the prevention and treatment of LRD.

Biological organisms are multifaceted, intricate systems where slight perturbations can result in extensive changes in gene expression, protein abundance and/or activity, and metabolic flux. These changes occur at different timescales, spatially across cells of heterogeneous origins, and within single-cells. Hence, multimodal measurements at the smallest biological scales are necessary to capture dynamic changes in heterogeneous biological systems. Of the analytical techniques used to measure biomolecules, mass spectrometry (MS) has proven to be a powerful option due to its sensitivity, robustness, and flexibility with regard to the breadth of biomolecules that can be analyzed. Recently, many studies have coupled MS to other analytical techniques with the goal of measuring multiple modalities from the same single-cell. It is with these concepts in mind that we focus this review on MS-enabled multiomic measurements at single-cell or near-single- cell resolution.

Targeting metalloproteinases (MPs) has been the center of attention for developing therapeutics due to their contribution to a wide range of diseases, including cancer, cardiovascular, neurodegenerative disease, and preterm labor. Protein-based MP inhibitors offer higher stability and selectivity, which is critical for developing efficient therapeutics with low off-target effects. Tissue inhibitors of metalloproteinases (TIMPs), natural inhibitors of MPs, and antibodies provide excellent protein scaffolds for engineering selective or multispecific MP inhibitors. Advances in protein engineering and design techniques, such as rational design and directed evolution using yeast display to develop potent MP inhibitors, are discussed, including but not limited to loop grafting, swapping, and counterselective selection.

Enzymes are widely used as catalysts in the chemical and pharmaceutical industries. While successful in many situations, they must usually be adapted to operate efficiently under nonnatural conditions. Enzyme engineering allows the creation of novel enzymes that are stable at elevated temperatures or have higher activities and selectivities. Current enzyme engineering techniques require the production and testing of enzyme variant libraries to identify members with desired attributes. Unfortunately, traditional screening methods cannot screen such large mutagenesis libraries in a robust and timely manner. Droplet-based microfluidic systems can produce, process, and sort picoliter droplets at kilohertz rates and have emerged as powerful tools for library screening and thus enzyme engineering. We describe how droplet-based microfluidics has been used to advance directed evolution.

Monoclonal antibodies have revolutionized the treatment of human diseases, which has made them the fastest-growing class of therapeutics, with global sales expected to reach $346.6 billion USD by 2028. Advances in antibody engineering and development have led to the creation of increasingly sophisticated antibody-based therapeutics (e.g. bispecific antibodies and chimeric antigen receptor T cells). However, approaches for antibody discovery have remained comparatively grounded in conventional yet reliable in vitro assays. Breakthrough developments in high-throughput single B-cell sequencing and immunoglobulin proteomic serology, however, have enabled the identification of high-affinity antibodies directly from endogenous B cells or circulating immunoglobulin produced in vivo. Moreover, advances in artificial intelligence offer vast potential for antibody discovery and design with large-scale repertoire datasets positioned as the optimal source of training data for such applications. We highlight advances and recent trends in how these technologies are being applied to antibody repertoire analysis.

Polyethylene terephthalate (PET) has revolutionized the industrial sector because of its versatility, with its predominant uses in the textiles and packaging materials industries. Despite the various advantages of this polymer, its synthesis is, unfavorably, tightly intertwined with nonrenewable fossil resources. Additionally, given its widespread use, accumulating PET waste poses a significant environmental challenge. As a result, current research in the areas of biological recycling, upcycling, and de novo synthesis is intensifying. Biological recycling involves the use of micro-organisms or enzymes to breakdown PET into monomers, offering a sustainable alternative to traditional recycling. Upcycling transforms PET waste into value-added products, expanding its potential application range and promoting a circular economy. Moreover, studies of cascading biological and chemical processes driven by microbial cell factories have explored generating PET using renewable, biobased feedstocks such as lignin. These avenues of research promise to mitigate the environmental footprint of PET, underlining the importance of sustainable innovations in the industry.