Muramyl dipeptide

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Structural formula of MDP

Muramyl dipeptide (chemically: N-acetyl-muramyl- L- alanyl- D- iso-glutamine; MDP for short) is a naturally occurring fragment of the peptidogyl can , a component of the cell wall of most gram-positive and gram-negative bacteria .

discovery

MDP was discovered in 1974 as the minimal structure for the efficiency of Freund's complete adjuvant , one of the most powerful adjuvants for triggering an immune response. MDP triggers humoral and cellular immune responses , but no antibody production.

Signal path

The binding of MDP to the cytosolic receptor NOD2 triggers a pro-inflammatory immune response. Here z. B. Inflammation mediators (IL-8, IL-1β, TNF) are secreted, autophagy induced and antimicrobial peptides produced. The NOD2 variant L1007fsinsC leads to incorrect detection of MDP and an altered immune response.

Use in medicine

Because of its adjuvant activity, MDP has been discussed for enhancing the immune response, e.g. B. in vaccinations. However, MDP was himself to pyrogenic and had in animal experiments in rabbits , a uveitis caused. Therefore derivatives such as threonyl -MDP were developed. It was tested as a component of a first adjuvant based on an oil-in-water emulsion (as an alternative to water-in-oil emulsions). The SAF adjuvant ( Syntex adjuvant formulation ) developed here contained a hydrogenated form of squalene and threonyl-MDP. However, clinical trials showed too high reactogenicity, and without MDP the adjuvant was far weaker.
Another derivative, muramyl tripeptide phosphatidylethanolamine (MTP-ME, mifamurtide ), was tested as an adjuvant as a component of a squalene-based oil-in-water emulsion. This was also much too reactogenic. Therefore, the further development and research of adjuvants with MDP was discontinued, without these immunostimulants the development of oil-in-water-based adjuvants in the form of MF59 culminated .
  • in tumor therapy:
The MDP derivative mifamurtide is used to treat osteosarcomas in children, adolescents and young adults.

Individual evidence

  1. ↑ a b Naohiro Inohara et al .: Host Recognition of Bacterial Muramyl Dipeptide Mediated through NOD2 IMPLICATIONS FOR CROHN'S DISEASE . In: Journal of Biological Chemistry . tape 278 , no. 8 , February 21, 2003, p. 5509-5512 , doi : 10.1074 / jbc.C200673200 , PMID 12514169 .
  2. ↑ Stephen E. Girardin et al .: Nod2 Is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) Detection . In: Journal of Biological Chemistry . tape 278 , no. 11 , March 14, 2003, p. 8869-8872 , doi : 10.1074 / jbc.C200651200 , PMID 12527755 .
  3. ↑ Farielle Ellouz et al .: Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives . In: Biochemical and Biophysical Research Communications . tape 59 , no. 4 , August 19, 1974, p. 1317-1325 , doi : 10.1016 / 0006-291X (74) 90458-6 .
  4. ↑ Claude Merser, Pierre Sinaÿ, Arlette Adam: Total synthesis and adjuvant activity of bacterial peptidoglycan derivatives . In: Biochemical and Biophysical Research Communications . tape 66 , no. 4 , October 27, 1975, p. 1316-1322 , doi : 10.1016 / 0006-291X (75) 90503-3 .
  5. ↑ HS Warren, FR Vogel, LA Chedid: Current Status of Immunological Adjuvants . In: Annual Review of Immunology . tape 4 , no. 1 , 1986, pp. 369-388 , doi : 10.1146 / annurev.iy.04.040186.002101 , PMID 2871847 .
  6. ↑ Joseph P. Boyle, Rhiannon Parkhouse, Tom P. Monie: Insights into the molecular basis of the NOD2 signaling pathway . In: Open Biology . tape 4 , no. 12 , December 1, 2014, p. 140178 , doi : 10.1098 / rsob.140178 , PMID 25520185 .
  7. ^ A b c Manmohan Singh: Vaccine Adjuvants and Delivery Systems . John Wiley & Sons, 2007, ISBN 978-0-470-13492-4 , pp. 117 .
  8. ↑ a b c Stanley A. Plotkin et al .: Plotkin's Vaccines . 7th edition. Elsevier, Philadelphia 2017, ISBN 978-0-323-35761-6 , pp. 67 ( elsevier.com ).
  9. ↑ James E. Frampton: Mifamurtide . In: Pediatric Drugs . tape 12 , no. 3 , 2010, p. 141-153 , doi : 10.2165 / 11204910-000000000-00000 .