Dataset Information

7-Fluorosialyl Glycosides Are Hydrolysis Resistant but Readily Assembled by Sialyltransferases Providing Easy Access to More Metabolically Stable Glycoproteins.

ABSTRACT: The maintenance of therapeutic glycoproteins within the circulatory system is associated, in large part, with the integrity of sialic acids as terminal sugars on the glycans. Glycoprotein desialylation, either by spontaneous cleavage or through host sialidases, leads to protein clearance, mainly through the liver. Thus, the installation of minimally modified sialic acids that are hydrolysis-resistant yet biologically equivalent should lead to increased circulatory half-lives and improved pharmacokinetic profiles. Here we describe the chemoenzymatic synthesis of CMP-sialic acid sugar donors bearing fluorine atoms at the 7-position, starting from the corresponding 4-deoxy-4-fluoro-N-acetylhexosamine precursors. For the derivative with natural stereochemistry we observe efficient glycosyl transfer by sialyltransferases, along with improved stability of the resultant 7-fluorosialosides toward spontaneous hydrolysis (3- to 5-fold) and toward cleavage by GH33 sialidases (40- to 250-fold). Taking advantage of the rapid transfer of 7-fluorosialic acid by sialyltransferases, we engineered the O-glycan of Interferon ?-2b and the N-glycans of the therapeutic glycoprotein ?1-antitrypsin. Studies of the uptake of the glyco-engineered ?1-antitrypsin by HepG2 liver cells demonstrated the bioequivalence of 7-fluorosialic acid to sialic acid in suppressing interaction with liver cell lectins. In vivo pharmacokinetic studies reveal enhanced half-life of the protein decorated with 7-fluorosialic acid relative to unmodified sialic acid in the murine circulatory system. 7-Fluorosialylation therefore offers considerable promise as a means of prolonging circulatory half-lives of glycoproteins and may pave the way toward biobetters for therapeutic use.

SUBMITTER: Geissner A

PROVIDER: S-EPMC7908025 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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7-Fluorosialyl Glycosides Are Hydrolysis Resistant but Readily Assembled by Sialyltransferases Providing Easy Access to More Metabolically Stable Glycoproteins.

Geissner Andreas A Baumann Lars L Morley Thomas J TJ Wong Andrew K O AKO Sim Lyann L Rich Jamie R JR So Pauline P L PPL Dullaghan Edie M EM Lessard Etienne E Iqbal Umar U Moreno Maria M Wakarchuk Warren W WW Withers Stephen G SG

ACS central science 20210119 2

The maintenance of therapeutic glycoproteins within the circulatory system is associated, in large part, with the integrity of sialic acids as terminal sugars on the glycans. Glycoprotein desialylation, either by spontaneous cleavage or through host sialidases, leads to protein clearance, mainly through the liver. Thus, the installation of minimally modified sialic acids that are hydrolysis-resistant yet biologically equivalent should lead to increased circulatory half-lives and improved pharmac ...[more]

PMID: 33655072

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Project description:OBJECTIVE:Improving access to effective and safe medicines is one of the major goals of all health systems. To achieve this goal, assessment is a fundamental phase of national medicine programs for access improvement. Collecting and compiling applicable indicators and impart a comprehensive framework for assessing access to medicine, are the aims of this study. METHODS:To investigate the published materials on access to medicines framework or indicators, a literature review with a systematic search was conducted using PubMed/ Medline, Scopus, and Google Scholar databases. The results were completed with a general search of documents in Iran Food and Drug Administration (IRFDA). Two independent researchers reviewed all the articles and documents. Thereafter the related indicators were extracted. In focused group discussion of academics and IRFDA experts, duplicate entries or ineffectual concepts were cleaned from the preliminary indicators. In the next step, Delphi questionnaire was sent to the 17 experts that work in academia, Social Security Insurance, IRFDA, Ministry of Health and Iran Pharmacist Association. The results of Delphi technique were finalized in an expert panel. RESULTS:One hundred and thirty one indicators were found in systematic search. After primary extraction of related indicators, 77 indicators were sent to the 17 experts in a Delphi form. The results of Delphi were finalized in a specialized-working group and 67 indicators were accepted in 5 categories including physical availability and geographical accessibility (19 indicators), affordability (23 indicators), human resources (4 indicators), quality and safety (5 indicators), information and rational use (16 indicators). CONCLUSION:The indicators that inclusively assess the full access to medicine in the concept of rational use have been categorized into five categories in this study. To determine the access to medicine status in each country further local surveys are necessary for all several indicators in each category. Graphical abstract The graphical abstract of accomplished steps.

Project description:BackgroundThe COVID-19 pandemic has adversely affected health care systems and dialysis access care in the US and across the globe. Beyond the initial challenges posed by the pandemic and despite the actions taken by health care leaders/organizations/professional societies such as the "Maintaining Lifelines for ESKD Patients" joint statement, there continues to be delays in providing timely care and performing elective and emergent dialysis access procedures worldwide. The aim of this study was to assess the global challenges associated with providing dialysis vascular access care across the international vascular access community during the pandemic.MethodsThe American Society of Diagnostic and Interventional Nephrology (ASDIN) conducted an online survey in 2021, that was administered to an expert panel of dialysis vascular access specialists and global leaders spanning across the international community. The respondents who are members of ASDIN, Association of Vascular Access and InTerventionAl Renal physicians (AVATAR), Asia Pacific Society of Dialysis Access (APSDA), Peruvian Vascular Access Society (APDAV), and Australia/New Zealand Society of Interventional Nephrology (ANZSIN) reported their experiences in the care of dialysis vascular access, practice patterns, and challenges faced during the COVID pandemic.ResultsOf the 53 individual surveys sent, 16 were opened and 11 (69%) responses were received from across the world and from different practice settings. The survey revealed the continued challenges facing the international community, the stark disparities in care delivery, supply chain disruption and logistical, regulatory, and financial issues that the global community continues to face in the ongoing pandemic.ConclusionsThe COVID19 pandemic is far from over, and the challenges and barriers to providing dialysis access care seen on the initial ASDIN survey in the US seem to extend across the globe. We describe those results and discuss options, opportunities, and innovative tools to provide dialysis and access care during these trying times.

Dataset Information

7-Fluorosialyl Glycosides Are Hydrolysis Resistant but Readily Assembled by Sialyltransferases Providing Easy Access to More Metabolically Stable Glycoproteins.

Publications

7-Fluorosialyl Glycosides Are Hydrolysis Resistant but Readily Assembled by Sialyltransferases Providing Easy Access to More Metabolically Stable Glycoproteins.

Similar Datasets

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