Structure-activity relationship in NOD2 agonistic muramyl dipeptides

Abstract

Nucleotide-binding oligomerization domain 2 (NOD2) is a receptor of the innate immune system that is capable of perceiving bacterial and viral infections. Muramyl dipeptide (MDP, N-acetyl muramyl L-alanyl-d-isoglutamine), identified as the minimal immunologically active component of bacterial cell wall peptidoglycan (PGN) is recognized by NOD2. In terms of biological activities, MDP demonstrated vaccine adjuvant activity and stimulated non-specific protection against bacterial, viral, and parasitic infections and cancer. However, MDP has certain drawbacks including pyrogenicity, rapid elimination, and lack of oral bioavailability. Several detailed structure-activity relationship (SAR) studies around MDP scaffolds are being carried out to identify better NOD2 ligands. The present review elaborates a comprehensive SAR summarizing structural aspects of MDP derivatives in relation to NOD2 agonistic activity.

Keywords: Innate immunity; MDP; Muramyl dipeptide; NOD2; PAMPs; Vaccine adjuvant.

Fig. 1.

Types of NLRs.

Fig. 2.

Muramyl dipeptide (MDP) structure.

Fig. 3.

Structure and signalling pathway of NOD2 activation.

Fig. 4.

Synthetic derivatives of MDP in clinical use.

Fig. 5.

Analogs of MDP having modifications at the C1 and C2 positions. *R₁ and R₂ modifications in compounds 5-24 are shown in tabular format.

Fig. 6.

C2 modified MDP analogs by Melnyk and Reddy et al.

Fig. 7.

Modifications at the C4 position of the carbohydrate moiety.

Fig. 8.

NOD2 agonists having modifications at the C6 position of MDP. ^ΦL-D and L-L are the stereochemistry of alanine (first amino acid AA1) and glutamine (second amino acid AA2).

Fig. 9.

MDP analogs having modifications at the C6 position. *R₁, R₂ and R₃ modifications in compounds 55-59 are shown in tabular format.

Fig. 10.

MDP analogs having modifications at the C6 position by Azuma et al.

Fig. 11.

Modifications at the first amino acid.

Fig. 12.

MDP analogs having modification at the D-iso-glutamine residue (second amino acid) of the peptide part. *The modifications at X and Y in 101-116 are shown in tabular format.

Fig. 13.

MDP analogs having modification at the D-iso-glutamine residue by Rubino et al. and Mhamane et al.

Fig. 14.

Modification at dipeptide and carbohydrate moiety.

Fig. 15.

Carbocyclic analogs of MDP.

Fig. 16.

Substituted benzoyl containing desmuramylpeptides.

Fig. 17.

Desmuramylpeptides having hydrophilic arene as a substitute for carbohydrate moiety.

Fig. 18.

Saccharin and indole heterocycles containing desmuramylpeptides.

Fig. 19.

Novel desmuramylpeptides with ester functionalities.

Fig. 20.

Desmuramylpeptides and their NOD2 agonistic activity.

Fig. 21.

Desmuramylpeptides having modifications at the C3 and C4 position along with modifications at the first amino acid.

Fig. 22.

Desmuramylpeptides having cinnamoyl moiety and variation of first amino acid.

Fig. 23.

Desmuramylpeptides having C3 and C4 substituted cinnamoyl moiety.

Fig. 24.

Desmuramylpeptides having modifications

Fig. 25.

Desmuramylpeptides having modifications at the second amino acid. R₁ and R₂ are the modifications at the second amino acid (AA2) in compounds 290-302 and R is the modification at AA2 in compounds 303-308

Fig. 26.

Mannosylated desmuramylpeptides.

Fig. 27.

Peptidoglycan fragment library containing two types of glycan sequences.

Fig. 28.

Muramyl dipeptide antigen conjugates.

Fig. 29.

Muramyl dipeptide conjugates with biomolecules and small molecule drugs.

Fig. 30.

Muropeptides containing meso-DAP.

Fig. 31.

SAR in muramyl dipeptides.

Fig. 32.

SAR in desmuramylpeptides.