Synthesis of asymmetrical multiantennary human milk oligosaccharides

Each year over 3 million people die from infectious diseases with most of these deaths being poor and young children who live in low- and middle-income countries. Infectious diseases emerge for a multitude of reasons. On the social front, reasons include a breakdown of public health standards, international travel, and immigration (for financial, civil, and social reasons). At the molecular level, the modern rise of infectious diseases is tied to the juxtaposition of drug-resistant pathogens and a lack of new antimicrobials. The consequence is the possibility that humankind will return to the preantibiotic era wherein millions of people will perish from what should be trivial illnesses. Given the stakes, it is imperative that the chemistry community take leadership in delivering new antibiotic leads for clinical development. We believe this can happen through innovation in two areas. First is the development of novel chemical scaffolds to treat infections caused by multidrug-resistant pathogens. The second area, which is not exclusive to the first, is the generation of antibiotics that do not cause collateral damage to the host or the host’s microbiome. Both can be enabled through advances in chemical synthesis. It is with this general philosophy in mind that we hypothesized human milk oligosaccharides (HMOs) could serve as novel chemical scaffolds for antibacterial development. We provide herein a personal account of our laboratory’s progress toward the goal of using HMOs as a defense against infectious diseases.

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“…79 It is our hope that the high-level nature of the problem will continue to inspire novel strategies and tactics to produce complex HMOs. 77,78 …”

Section: Challenges and Future Opportunitiesmentioning

confidence: 99%

The Human Milk Glycome as a Defense Against Infectious Diseases: Rationale, Challenges, and Opportunities

Craft

Townsend

2017

ACS Infect. Dis.

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“…Analysis of these models suggested glycosyltransferase genes, thus providing a clearer picture of the enzymes and regulators of HMO biosynthesis in mammary epithelial cells. The clarification of the pathways and enzymes involved in HMO biosynthesis will be an invaluable resource to help (1) discover the maternal genetic basis of healthimpacting 1,2,5,6,37-46 HMO composition heterogeneity 7,26,47,48 and (2) drive chemoenzymatic synthesis [49][50][51][52][53] and metabolic engineering for manufacturing HMOs for food ingredients, supplements and potential therapeutics [54][55][56][57][58][59] (see supplemental discussion).…”

Section: Discussionmentioning

confidence: 99%

Elucidating Human Milk Oligosaccharide biosynthetic genes through network-based multiomics integration

Kellman¹,

Richelle²,

Yang

et al. 2020

Preprint

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Human Milk Oligosaccharides (HMOs) are abundant carbohydrates fundamental to infant health and development. Although these oligosaccharides were discovered more than half a century ago, their biosynthesis in the mammary gland remains largely uncharacterized. Here, we used a systems biology framework that integrated glycan and RNA expression data to construct an HMO biosynthetic network and predict glycosyltransferases involved. To accomplish this, we constructed models describing the most likely pathways for the synthesis of the oligosaccharides accounting for >95% of the HMO content in human milk. Through our models, we propose candidate genes for elongation, branching, fucosylation, and sialylation of HMOs. We further explored selected enzyme activities through kinetic assay and their co-regulation through transcription factor analysis. These results provide the molecular basis of HMO biosynthesis necessary to guide progress in HMO research and application with the ultimate goal of understanding and improving infant health and development.Significance statementWith the HMO biosynthesis network resolved, we can begin to connect genotypes with milk types and thereby connect clinical infant, child and even adult outcomes to specific HMOs and HMO modifications. Knowledge of these pathways can simplify the work of synthetic reproduction of these HMOs providing a roadmap for improving infant, child, and overall human health with the specific application of a newly limitless source of nutraceuticals for infants and people of all ages.

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“…The flexible motif syntax enables the automated generation of novel motif definitions that can account for unforeseen fine-specificities. This capability could be useful for characterizing protein binding to unusual glycans, as in a previous application of the method (29) to glycans with unequal extensions and substituents on each branch (30). The method identified features that would not have been practically analyzable using manual analyses or previous modes of representing motifs.…”

Section: Fig 2 Defining Motifs and Families Of Motifs A Motif Typmentioning

confidence: 99%

“…Synthetic strategies address these limitations and are making good progress. New synthetic methods have provided structures that previously were difficult to synthesize, such as asymmetricallybranched N-glycans (29,(71)(72)(73), which were useful for producing arrays of human milk oligosaccharides (30). Several groups have developed arrays for additional classes such as sialylated structures (74 -76), plant cell-wall glycans (77), and microbial glycans (8,78,79).…”

Section: Fig 2 Defining Motifs and Families Of Motifs A Motif Typmentioning

confidence: 99%

Advances in Tools to Determine the Glycan-Binding Specificities of Lectins and Antibodies

Haab¹,

Klamer²

2020

Molecular & Cellular Proteomics

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Proteins that bind carbohydrate structures can serve as tools to quantify or localize specific glycans in biological specimens. Such proteins, including lectins and glycan-binding antibodies, are particularly valuable if accurate information is available about the glycans that a protein binds. Glycan arrays have been transformational for uncovering rich information about the nuances and complexities of glycan-binding specificity. A challenge, however, has been the analysis of the data. Because protein-glycan interactions are so complex, simplistic modes of analyzing the data and describing glycan-binding specificities have proven inadequate in many cases. This review surveys the methods for handling high-content data on protein-glycan interactions. We contrast the approaches that have been demonstrated and provide an overview of the resources that are available. We also give an outlook on the promising experimental technologies for generating new insights into protein-glycan interactions, as well as a perspective on the limitations that currently face the field.

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Synthesis of asymmetrical multiantennary human milk oligosaccharides

Cited by 123 publications

References 40 publications

The Human Milk Glycome as a Defense Against Infectious Diseases: Rationale, Challenges, and Opportunities

The Human Milk Glycome as a Defense Against Infectious Diseases: Rationale, Challenges, and Opportunities

Elucidating Human Milk Oligosaccharide biosynthetic genes through network-based multiomics integration

Advances in Tools to Determine the Glycan-Binding Specificities of Lectins and Antibodies

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