%0 Journal Article
%T Preparation and Immunomodulatory Properties of Modified Peptidoglycan Fragments
%A Ribi£¿
%A R.
%A Tomi£¿
%A S.
%J Kemija u Industriji
%D 2013
%I Croatian Society of Chemical Engineers
%X Immunostimulators, known also as adjuvants, are added to vaccines to accelerate, extend or amplify the specific immune reaction to a specific antigen. One well known class of immuno- modulating compounds is based on muramylpeptides which are fragments of peptidoglycans, natural polymers that build up the cell wall of bacteria. Muramyldipeptide, N-acetyl- muramyl-L-alanyl-D-isoglutamine (MDP, Fig. 1) is the smallest structural unit of the peptidoglycan monomer (PGM, Fig. 2) which shows immunostimulating activity. PGM isolated from Brevibacterium divaricatum, acts in itself as an effective adjuvant, and several derivatives were prepared to study the possible influence of different substituents on the immunomodulatory activity. Thus, lipophilic derivativestert-butyloxycarbonyl-L-tyrosyl-PGM and (adamant- 1-yl)acetyl-PGM (Fig. 3) were prepared and their activities studied. They were also shown to be good substrates for N-acetylmuramyl-L-alanine amidase from human serum (Scheme 1) which specifically hydrolyzes the lactylamide bond. MDP which is an integral part of PGM and proven to be an effective adjuvant was further synthetically modified and obtained derivatives tested as possible immunomodulators. Romutide (MDP-Lys(L18)), approved by Food and Drug Administration (FDA), and mifamurtide (L-MTP-PE), approved by European Medicines Agency (EMA), highlight among many other MDP derivatives (Fig. 4). Since N-acetylglucosamine in the structure of MDP is not essential for the immunostimulating effect, desmuramyldipeptides (Fig. 5) with different acyl groups at N-terminus of L-Ala-D-isoGln dipeptide were prepared. In ada mantyl desmuramyldipeptides such as adamantylamide dipeptide (Fig 6), adamantyl tripeptides (Fig. 7) and desmuramylpeptides with (adamant-1-yl)carboxyamido group (Fig. 8), lipophilic adamantane moiety is bound to the dipeptide part. Binding of some specific sugars to immune active substances may help their targeted delivery. An example is mannose which enables man- nosylated compounds to interact with lectins specific for mannose, such as mannose receptors (MR) expressed at macrophages and dendritic cells. Therefore, it is possible to increase the activity of the parent immunologically active compound by mannosylation. One of the ways is the preparation of mannosylated liposomes by using mannosylated lipids (Fig. 9). Mannosylation can also influence the direction of the immune reaction. This is shown by the examples of mannosylated PGM and adamantyl tripeptides. Mannosylated PGM derivatives (Scheme 2) are the first PGM derivatives comprising carbohy
%K Immunostimulators
%K mannosylation
%U http://pierre.fkit.hr/hdki/kui/vol62/broj1-2/19.pdf