Chemoenzymatic Synthesis of a Library of 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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“…33,35 For some of the core glycans which are readily available from an abundant natural source, purification followed by additional processing such as trimming using exoglycosidases or acid hydrolysis 36–38 is a good alternative. We name the strategy Core Isolation/Enzymatic Extension (CIEE) and use it for the desired biantennary N -glycans.…”

Section: Introductionmentioning

confidence: 99%

Identification of the binding roles of terminal and internal glycan epitopes using enzymatically synthesized N-glycans containing tandem epitopes

Liu

et al. 2016

Org. Biomol. Chem.

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Glycans play diverse roles in a wide range of biological processes. Research on glycan-binding events is essential for learning their biological and pathological functions. However, the functions of terminal and internal glycan epitopes exhibited during binding with glycan-binding proteins (GBPs) and/or viruses need to be further identified. Therefore, a focused library of 36 biantennary asparagine (Asn)-linked glycans with some presenting tandem glycan epitopes was synthesized via a combined Core Isolation/Enzymatic Extension (CIEE) and one-pot multienzyme (OPME) synthetic strategy. These N-glycans include those containing a terminal sialyl N-acetyllactosamine (LacNAc), sialyl Lewis x (sLex) and Siaα2–8-Siaα2–3/6-R structures with N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc) sialic acid form, LacNAc, Lewis x (Lex), α-Gal, and Galα1–3-Lex; and tandem epitopes including α-Gal, Lex, Galα1–3-Lex, LacNAc, and sialyl LacNAc, presented with an internal sialyl LacNAc or 1–2 repeats of an internal LacNAc or Lex component. They were synthesized in milligram-scale, purified to over 98% purity, and used to prepare a glycan microarray. Binding studies using selected plant lectins, antibodies, and viruses demonstrated, for the first time, that when interpreting the binding between glycans and GBPs/viruses, not only the structure of the terminal glycan epitopes, but also the internal epitopes and/or modifications of terminal epitopes needs to be taken into account.

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“…Then, the glycan products were subsequently purified under the monitor of A 210nm according to the retention time from the analytical run, as previously reported 19,28,29 (Supplementary Information III). The collected substance was lyophilized and analyzed by MS (Supplementary Information VIII).…”

Section: Resultsmentioning

confidence: 99%

Decoding glycan protein interactions by a new class of asymmetric N-glycans

Liu

et al. 2017

Org. Biomol. Chem.

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N -glycans are normally involved in crucial physiological and disease processes by interactions with glycan binding proteins. So far structurally defined N-glycans are good candidates for glycan binding study. Herein, a class of homogeneous asymmetric N-glycans was synthesized by coupling glycan-oxazoline and N-glycans using EndoM N175Q catalyzed quick glycan extension. Branch-biased binding and spacial inhibition caused by bulky group on the other branch of N-glycan were observed in glycan protein interactions involving lectins and these glycans by glycan microarray study. These new compounds are valuable for functional glycomic studies to better understand new functions of glycans and glycan-binding proteins.

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Chemoenzymatic Synthesis of a Library of Human Milk Oligosaccharides

Cited by 84 publications

References 48 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

Identification of the binding roles of terminal and internal glycan epitopes using enzymatically synthesized N-glycans containing tandem epitopes

Decoding glycan protein interactions by a new class of asymmetric N-glycans

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