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Synthesis 2024; 56(04): 539-548
DOI: 10.1055/a-2004-5883
special topic
Synthetic Development of Key Intermediates and Active Pharmaceutical Ingredients (APIs)

A Robust, Gram-Scale and High-Yield Synthesis of MDP Congeners for Activation of the NOD2 Receptor and Vaccine Adjuvantation

Farooq-Ahmad Khan  ∗
a   Third World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
b   H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
,
Sana Yaqoob‡
a   Third World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
b   H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
,
Muhammad Wasim Qasim‡
a   Third World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
b   H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
,
Shujaat Ali
a   Third World Center for Science and Technology, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
b   H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
,
Yan Wang∗
b   H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
,
Zi-Hua Jiang∗
c   Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, Ontario, P7B 5E1, Canada
› Author AffiliationsThe authors are grateful for the financial support from Sindh Higher Education Commission (project number SHEC/SRSP/MS-1/7/2020-21), and for co-funding from the Pakistan Science Foundation (project number PSF/CRP/S-ICCBS/T-Helix-(175)).
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Abstract

The bacterial peptidoglycan (PGN) constituent muramyl dipeptide (MDP) and its congeners possess immuno-adjuvant activity, and find applications in vaccines to potentiate the immune response of antigens. It confers non-specific resistance towards pathogenic infections and defense against tumors. In this work, the parent MDP molecule is re-designed by replacing its carbohydrate moiety with an immunoregulatory xanthine scaffold, while conserving the l-d configuration of the pharmacophore. Alkyl chains are introduced at the C-terminus of d-isoglutamine to help the molecules access cytoplasmic NOD2 receptors and activate the innate immune system. Lipophilic MDP congeners are thus obtained by adopting a direct or indirect convergent synthetic route with overall yields of >50%. We found that an indirect approach can reliably be implemented on gram scale, thereby unlocking access to substantial amounts of pathogen-associated molecular patterns for in vivo studies, which will accelerate the development of NOD2 immuno-adjuvants against viral and bacterial infections.

Key words

NOD2 - vaccine - adjuvant - muramyl - peptides

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2004-5883.
  • Supporting Information


Publication History

Received: 04 November 2022

Accepted after revision: 29 December 2022

Accepted Manuscript online:
29 December 2022

Article published online:
02 February 2023

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