Muramyl Dipeptide and its Derivatives: Peptide Adjuvant in Immunological Disorders and Cancer Therapy

Abstract

Muramyl dipeptide (MDP) is a synthetic immunoreactive peptide consisting of N-acetyl muramic acid attached to a short amino acid chain of L-Ala-D-isoGln. It was first identified in bacterial cell wall peptidoglycan as an active component in Freund’s complete adjuvant. In the cell, MDP is detected by NOD2, a cytoplasmic receptor belonging to the human innate immune system. NOD2 mutations are frequently observed in patients with Crohn’s disease, an autoimmune disorder, suggesting the significance of the MDP-NOD2 pathway in activating immunity. For this reason, structural modifications of MDP and its derivatives have been extensively studied in an attempt to increase adjuvant activity and boost the immune response effectively for clinical use in the treatment of cancer and other diseases. This review summarizes the synthetic chemistry of MDP and its derivatives and discusses their pharmacological action and stereoselective synthesis.

Proteasomal Degradation of Nod2 Protein Mediates Tolerance to Bacterial Cell Wall Components

“…Nod2, a cytoplasmic NLR, senses the component of bacterial cell wall peptidoglycan called MDP, which consists of N-acetylmuramyl-L-Ala-D-Gln (28). The N-terminal part of Nod2 contains two caspase recruitment domains (CARDs) responsible for interacting with a downstream effector, a centrally located NBD required for nucleotide binding and self-oligomerization, and a C-terminal portion containing LRRs involved in ligand recognition (29).…”

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

“…In most Gram-negative and -positive bacteria the PGN represents a key component of the cell wall with an important impact on maintaining the structural integrity of plasma membranes and anchoring cell components such as lipoproteins [2]. The pivotal role of PGN in the bacterial pathogenesis is clearly highlighted by the fact, that the most frequently used antibiotics are targeting the PGN biosynthesis pathway [13].…”

“…MDP consists of Nacetylmuramic acid linked to the two amino acids: D-Ala and D-isoGln (or D-Glu) [15]. The structure of MDP is unique in the way that MDP analogues composed of other amino acid leads to a reduced or inhibited ability to induce a biological response, also called "the priming effect" [2,16].…”

“…Muramyl dipeptide (MDP) is an immunoreactive peptide found in the peptidoglycan (PGN) motif which encodes "the building blocks" of bacterial cell walls [2]. MDP can activate several immunological signaling pathways, including the nucleotide oligomerization domain 2 (NOD2, a NLR member) dependent pathway via specific interaction between NOD2 and MDP; resulting in activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor which induces expression of pro-inflammatory cytokines [2].…”

“…MDP can activate several immunological signaling pathways, including the nucleotide oligomerization domain 2 (NOD2, a NLR member) dependent pathway via specific interaction between NOD2 and MDP; resulting in activation of nuclear factor-κB (NF-κB), a ubiquitous transcription factor which induces expression of pro-inflammatory cytokines [2]. Multiple studies have linked NOD2 to several severe immunological dysfunctions such as graft-versus-host disease [3], enhanced mortality during sepsis [4,5] , and Crohn's disease (CD) [6,7], indicating that MDP might play a pathophysiological role in these disorders.…”