Antigen-specific suppression of experimental autoimmune encephalomyelitis by a novel bifunctional peptide inhibitor: structure optimization and pharmacokinetics.
The objective of this study was to optimize the in vivo activity of proteolipid protein (PLP)-bifunctional peptide inhibitor (BPI) molecule to suppress experimental autoimmune encephalomyelitis (EAE) in SJL/J mice and evaluate pharmacokinetic profiles of PLP-BPI. PLP-BPI is constructed via conjugation of myelin PLP(139-151) with CD11a(237-246)-derived peptide (LABL) via a spacer. The hypothesis is that PLP-BPI binds simultaneously to major histocompatibility complex-II and intercellular adhesion molecule-1 on the antigen-presenting cell (APC) and inhibits the formation of the immunological synapse during T-cell and APC interactions. In this study, the structure of BPI was modified by varying the spacer and was evaluated in the EAE model. Intravenous injections of BPI derivatives inhibited the onset, severity, and incidence of EAE more effectively and induced a lower incidence of anaphylaxis than that produced by unmodified PLP-BPI. As anticipated, production of interleukin-17, a proinflammatory cytokine commonly found in elevated levels among multiple sclerosis (MS) patients, was significantly lower in Ac-PLP-BPI-PEG6- or Ac-PLP-BPI-NH(2)-2-treated mice than in phosphate-buffered saline-treated mice. These results suggest that BPI-type molecules can be modified to achieve more efficient and better tolerated BPI-based derivatives for the treatment of MS.
Ridwan
Rahmawati
R
Department of Pharmaceutical Chemistry, University of Kansas, Simons Research Laboratories, 2095 Constant Avenue, Lawrence, KS 66047, USA.
Kiptoo
Paul
P
Kobayashi
Naoki
N
Weir
Scott
S
Hughes
Michael
M
Williams
Todd
T
Soegianto
Rondang
R
Siahaan
Teruna J
TJ
D000707:Anaphylaxis / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D018845:CD11 Antigens / Q000737:chemistry*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D000939:Epitopes; D005260:Female; D020381:Interleukin-17 / Q000096:biosynthesis / Q000097:blood; D008297:Male; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000737:chemistry*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D018845:CD11 Antigens; D000939:Epitopes; D020381:Interleukin-17; D018991:Myelin Proteolipid Protein; D009842:Oligopeptides; D010446:Peptide Fragments