
Pentapeptide, targeting Serum Amyloid A and Amyloid β
suppresses /attenuates chronic inflammation, autoimmunity and neurodegeneration
Ma’ayan Shaked1 , Haim Ovadia2 , Keren-Or Amar1, Lora Eshkar –Sebban1 Shmuel Cohen1 , Michal Melamed1 , Jin Ryoun Kim 3 , Hanna Rosenmann4 ,Mary Cowman5, Ehud Cohen6 and David Naor1
1The Lautenberg Center of Immunology and Cancer Research ,Faculty of Medicine, Hebrew University of Jerusalem, Israel; 2Department of Neurology, Hadassah-Hebrew University Medical Center , Jerusalem ,Israel; 3Othmer-Jacobs Department of Chemical and Biological Engineering, Polytechnic Institute of New York University, Brooklyn, USA; 4Department of Neurology,The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center; 5Tandon School of Engineering, New York University, New York, NY, USA, 6Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel–Canada, Hebrew University, School of Medicine, Jerusalem, Israel;
Research Summary
5-mer peptide (MTADV-Methionin, Threonine, Alanine, Aspartic acid, Valine) was derived from a pro-inflammatory CD44 variant that expressed mostly, if not exclusively, in inflamed joints of a rheumatoid arthritis (RA) patient. The 5-MER MTADV is acetylated-N amidated-C to improve its stability. The MTADV interacting with the amyloid proteins, Serum Amyloid A (SAA), transthyretin and Apolipoprotein B, prevents/attenuates aggregation or polymerization of pathological amyloid proteins (SAA, Transthyretin). In addition, preliminary evidence revealed that it can also target Amyloid β. The MTADV peptide is polymerized in solution, displays β sheet configuration with alternating hydrophobic-hydrophilic amino acids, can cross cell membrane and lost its activity after amino acid scrambling. The 5-mer peptide exhibits therapeutic activity in mouse models of inflammatory diseases associated with the stress acute phase protein SAA, such as RA, inflammatory bowel disease (IBD) and multiple sclerosis (MS). For example, daily oral delivery of the MTADV peptide, starting 5 days after induction Experimental Autoimmune Encephalomyelitis (EAE) by MOG, attenuated limb paralysis in mouse model of MS. This finding further indicates that the peptide can tolerate the digestive system. The 5-mer peptide does not interfere with normal immune responses, such as delayed type hypersensitivity and does not generate, as expected, neutralizing antibodies after IP injection. C. elegans worms, expressing human Amyloid β transgene, which induces muscle paralysis, restore their movement potential after “feeding” with MTADV. Finally, a preliminary experiment reveals that Alzheimer’s -like mice (5XFAD transgenic mice)-restored their learning potential after daily IP injection with MTADV peptide. To this end, Alzheimer’s 5x FAD-transgenic mice treated with MTADV showed the same learning potential as wild type mice, whereas the Alzheimer‘s mice, that were not treated with the peptide display learning difficulties. Can the peptide therapeutic effects proven in animal model, be clinically translated? This question the focus of our current studies.
- Therapeutic effects of 5-MER peptide in inflammatory diseases
- Therapeutic effects of 5-MER peptide in neurodegenerative diseases
- 5-MER peptide as a cell penetrating therapeutic product
1. D. Naor and D. Sulitzeanu. Binding of radioiodinated bovine serum albumin to mouse spleen cells. Nature 214:687-688, 1967.
2. D. Naor, R.I. Mishell and L. Wofsy. Specific inhibition of an anti-hapten immune response by chemical modification of cells. J Immunol. 105:1322-1326, 1970.
3. D. Naor, C. Henry and H. Fudenberg. An in vitro immune response to penicillin. J. Immunol. 107:302-305, 1971
4. D. Naor and R. Mishell. In vitro immunity to TNP and penicillin. Specific inhibition with hapten-conjugated isologous red cells. J. Immunol. 108:246-252, 1972
5. S. Zolla, D. Naor and P. Tanapatchaiyapong. Cellular basis of of immunodepression in mice with plasmacytomas. J. Immunol. 112:2068-2076, 1974
6. S. Zolla and D. Naor. Restoration of immune competence in tolerant mice by parabiosis to normal mice. J. Exp. Med. 5:1421-1426, 1974
7. M. Kahan, R. Berman-Goldman, R. Saltoun and D. Naor. Studies on the immune response to fixed antigens. Preferential induction of helper function with heavily trinitrophenylated sheep erythrocytes and glutaraldehyde treated sheep erythrocytes. J. Immunol. 117:16-22, 1976
8. D. Naor, B. Bonavida and R.L. Walford. Autoimmunity and aging: The age-related response of a long-lived strain to trinitrophenylated syngeneic mouse red blood cells. J. Immunol. 117:2204-2208, 1976
9. D. Naor. Suppressor cells: Permitters and promoters of malignancy? Invited review. Adv. Cancer Res. 29:45-125, 1979
10. B. Leshem and D. Naor. Studies on the immune response to fixed antigens. III. Induction of helper function for antibody dependent cellular cytotoxicity responses. J. Immunol. 121:401-408, 1978
11. B. Devens and D. Naor. Immune responses to weakly immunogenic virally induced tumors. III. Genetically unrestricted cytolysis of allogeneic tumor target cells. J. Immunol. 122:1397-1401, 1979
12. D. Naor. Unresponsiveness to modified self antigens. A censorship mechanism controlling autoimmunity. Invited review. Immunological Reviews 50:187-226, 1980
13. B. Devens and D. Naor. Immune responses to weakly immunogenic virally induced tumors. VI. Comparison of the immune response of the hybrid to the immune responses of the parents reveals “hybrid responsiveness” effect. J. Immunol. 125:988-994. 1980
14. B.J. Kobrin, D. Naor and B.Y. Klein. Immunogenicity of subcellular fractions and molecular species of MuLV-induced tumors. II. Stimulation of syngeneic anti-tumor cell-mediated immune responses by subcellular fractions and molecular species of the Rauscher-virus-induced RBL5 tumor. J. Immunol. 125:1874-1882, 1981
15. V.E. Kelley, D. Naor, N. Tarcic, C.N. Gaulton, and T.B. Strom. Anti-Interleukein 2 receptor antibody suppresses delayed-type hypersensitivity to foreign and syngeneic antigens. J. Immunol. 137:2122-2124, 1986
16. D. Naor, G. Essery, N. Tarcic, M. Kahan, J.R. Lamb and M. Feldmann. Specific interactions between a human CD4+ clone and autologous CD4+ bifunctional immunoregulatory clones. Immunol. Rev. 116, 63-83, 1990
17. Zahalka, M.A. Okon, E. and Naor, D. Blocking lymphoma invasiveness with monoclonal antibody directed against the ß chain of the leukocyte adhesion molecule (CD18). J. Immunol. 150, 4466-4477, 1993
18. Zahalka, M.A., Okon, E., Gosslar, U., Holzmann, B. and Naor, D. Lymph node (but not spleen) invasion by murine lymphoma is both CD44 and Hyaluronate-dependent. J. Immunol. 154, 5345-5355, 1995
19. Naor, D., Vogt Sionov, R., and Ish-Shalom, D. CD44: Structure, function and its association with the malignant process. Adv. Cancer Res., 71, 241-319, 1997
20. Weiss, L., Slavin, S., Reich, S., Cohen, P., Shuster, S., Stern, R., Kaganovsky, E., Okon, E., Rubinstein, A.M., and Naor, D. Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with specific monoclonal antibody. Proc. Natl. Acad. Sci. USA. 97, 285-290, 2000
21. Wallach-Dayan, S. B., Grabovsky, V., Moll, J., Sleeman, J., Herrlich, P., Alon, R. and Naor, D. CD44-dependent lymphoma cell dissemination: a cell surface CD44 variant, rather than standard CD44, supports in vitro lymphoma cell rolling on hyaluronic acid substrate and its in vivo accumulation in the peripheral lymph nodes. Journal of Cell Science. 114, 3463-3477, 2001
22. Nedvetzki, S., Golan, I., Assayag, N., Gonen, E., Caspi, D., Gladnikoff M.Yayon,A., and Naor, D. A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of FGF with its receptor. J. Clin. Invest. 111, 1211-1220, 2003
23. Avigdor, A., Goichberg, P., Shivtiel, S., Dar, A., Peled, A., Samira, S., Kollet, O., Hershkoviz, R., Alon, R., Hardan, I., Ben-Hur, H., Naor, D., Nagler, A., and Lapidot, T. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to the bone marrow. Blood. 103,2981-2989,2004
24. Nedvetzki,S.,Gonen, E.,Assayag,N.,Reich, R,,Williams, R.O.,Thurmond,R.L.,Huang,J-F.,Neudecker,B.A.,F.,Wang,F-S.,Turley,E.A. and Naor,D. RHAMM,a receptor for hyaluronan-mediated motility compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy. PNAS 101,18081-18086,2004
25. Lora Eshkar Sebban, Denise Ronen, David Levartovsky, Ori Elkayam, Dan Caspi , Suhail Aamar, Howard Amital, Alan Rubinow, Ira Golan, David Naor, Yehiel Zick and Itshak Golan. The Involvement of CD44 and its Novel Ligand Galectin-8 in Apoptotic Regulation of Autoimmune Inflammation. J Immunol. 179:1225-1235, 2007
26. Vagima Y, Avigdor A, Goichberg P, Shivtiel S, Tesio M, Kalinkovich A, Golan K, Dar A, Kollet O, Petit I, Perl O, Rosenthal E, Resnick I, Hardan I, Gellman YN, Naor D, Nagler A, Lapidot T.MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization. J Clin Invest. 119:492-503, 2009
27. Girbl T, Hinterseer E, Grössinger EM, Asslaber D, Oberascher K, Weiss L, Hauser- Kronberger C, Neureiter D, Kerschbaum H, Naor D, Alon R, Greil R, Hartmann TN. CD40- mediated activation of chronic lymphocytic leukemia cells promotes their CD44-dependent adhesion to hyaluronan and restricts CCL21 induced motility. Cancer Res. 73(2):561-570, 2013
28. Nathalie Assayag-Asherie, Dror Sever, Marika Bogdani, Pamela Johnson, Talya Weiss, Ariel Ginzberg, Sharon Perles, Lola Weiss, Lora Eshkar Sebban, Eva A. Turley, Elimelech Okon, Itamar Raz, and David Naor. Can CD44 be a mediator of cell destruction ? the challenge of type 1 diabetes . PLoS One. 2015; 10(12): e0143589
29. Katia B, Naor D, Voevoda V, Ostrovsky O, Bitner H, Rosenberg E, Varda-Bloom N, Canaani J, Danilesko I, Shimoni A, and Nagler A., Dissecting the mechanisms involved in anti-human T-lymphocyteimmunoglobulin (ATG)-induced tolerance in the setting of allogeneic stem cell transplantation -potential implications for Graft versus Host Disease. Oncotarget, 8(53):90748-90765, 2017
Prof Mary Cowman, Tandon School of Engineering, New York University, New York, NY, United States
Dr Jin Ryoun Kim, Othmer-Jacobs Department of Chemical and Biological Engineering, Polytechnic Institute of New York University, Brooklyn, USA
Prof Hanna Rosenmann, Department of Neurology,The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center
Prof Dimitrios Karusis, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Dr Ibrahim Kassis, Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Prof Ehud Cohen, Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel–Canada, Hebrew University, School of Medicine, Jerusalem, Israel