Novel adjuvants assembled from a chemical construction set
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
To ensure that vaccines provide strong and lasting
immunization, it is often necessary to supplement the actual vaccine
(antigen) with additives that stimulate the immune system: adjuvants.
Today, only a few substances have been approved for use as adjuvants. In
the journal Angewandte Chemie, a research team has now introduced
a spectrum of potential adjuvants. They started with the immune
stimulant α-glactosyl ceramide (α-GalCer) and synthesized many
different variants from a set of four building blocks.
α-GalCer is a synthetic glycolipid (a compound made from
fat and sugar building blocks) based on similar compounds found in sea
sponges. It binds to CD1-d, a special receptor on antigen-presenting
cells. This activates certain immune cells and induces secretion of
cytokines that stimulate the immune system. In this way, this substance
boosts the immune response, assists in the battle against pathogens and
tumor cells, and reduces autoimmune reactions. Among the newly
synthesized α-GalCer analogs, the team led by Berhnard Westermann,
Daniel G. Rivera, and Carlos A. Guzmán from the Leibniz Institute of
Plant Biochemistry (Halle/Saale) and the Helmholtz Center for Infection
Research (Braunschweig) identified a number of compounds that have
significantly better and/or somewhat different activity.
The key to their success was the use of a special reaction
for the synthesis of the α-GalCer analogs: in a reaction known as the
Ugi four-component reaction, the target molecules are assembled in one
step from four individual building blocks. The team varied these four
components broadly in a combinatorial method and synthesized a
collection of different α-GalCer derivatives. In particular, they used a
functional group (N-substituent of the amide bond) that had not
been employed in the derivatization of α-GalCer before. This allowed the
team to introduce many different additional functionalities into their
α-GalCer analogs.
This strategy led to the discovery of compounds that
trigger stronger antigen-specific T-cell stimulation and higher antibody
reaction when they are administered to mice together with a model
antigen, either by injection or through the nasal mucosa. In addition,
various functionalized α-GalCer analogs demonstrated stronger adjuvant
activity in vitro and in animal studies that an α-GalCer
previously optimized (conjugated with polyethylene glycol) for this
purpose.
Interestingly, some of the new analogs showed somewhat
different effects on the immune system, making it possible to elicit
differently balanced immune responses through controlled variation of
the derivatization. This could make it possible to develop adjuvants
that can be tailored precisely to the requirements of the pathogens in
question. In addition, it may be possible to introduce an additional
binding site through which the antigen could be bound directly to the
adjuvant without compromising its effect—a requirement for the
development of self-adjuvating vaccines.
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About the Author
Prof. Bernhard Westermann works at the Leibniz-Institute of
Plant Biochemistry in the Department of Bioorganic Chemistry and holds
an appointment with the Martin-Luther-University, Halle-Wittenberg. His
major interests are in natural product chemistry, sustainable chemistry
and environmental benign multi-component reactions.
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