Document Type
Article
Abstract
Lipopolysaccharide (LPS) mimicry leading to toll-like receptor 4 (TLR4) active compounds has been so far based mainly on reproducing the lipid A portion of LPS. Our work led to a series of structurally simplified synthetic TLR4 agonists in preclinical development as vaccine adjuvants called FPs. FPs bind MD2/TLR4 similarly to lipid A, inserting the lipid chains in the MD2 lipophilic cavity. A strategy to improve FPs’ target affinity is introducing a monosaccharide unit in C6, mimicking the first sugar of the LPS core. We therefore designed a panel of FP derivatives bearing different monosaccharides in C6. We report here the synthesis and optimization of FPs’ C6 glycosylation, which presented unique challenges and limitations. The biological activity of glycosylated FP compounds was preliminarily assessed in vitro in HEK-Blue cells. The new molecules showed a higher potency in stimulating TLR4 activation when compared to the parent molecule while maintaining TLR4 selectivity.
Publication Date
10-3-2023
Publication Title
ACS Omega
E-ISSN
24701343
Volume
8
Issue
39
First Page
36412
Last Page
36417
DOI
10.1021/acsomega.3c05363
Funding Number
860325
Funding Sponsor
Horizon 2020 Framework Programme
Recommended Citation
Romerio, Alessio; Franco, Ana Rita; Shadrick, Melanie; Shaik, Mohammed Monsoor; Artusa, Valentina; Italia, Alice; Lami, Federico; Demchenko, Alexei V.; and Peri, Francesco, "Overcoming Challenges in Chemical Glycosylation to Achieve Innovative Vaccine Adjuvants Possessing Enhanced TLR4 Activity" (2023). Chemistry & Biochemistry Faculty Works. 100.
DOI: https://doi.org/10.1021/acsomega.3c05363
Available at:
https://irl.umsl.edu/chemistry-faculty/100