title: Comparison of Linear and Cyclic His-Ala-Val Peptides in Modulating the Blood-Brain Barrier Permeability: Impact on Delivery of Molecules to the Brain.
abstract: The aim of this study is to evaluate the effect of peptide cyclization on the blood-brain barrier (BBB) modulatory activity and plasma stability of His-Ala-Val peptides, which are derived from the extracellular 1 domain of human E-cadherin. The activities to modulate the intercellular junctions by linear HAV4 (Ac-SHAVAS-NH2), cyclic cHAVc1 (Cyclo(1,8)Ac-CSHAVASC-NH2), and cyclic cHAVc3 (Cyclo(1,6)Ac-CSHAVC-NH2) were compared in in vitro and in vivo BBB models. Linear HAV4 and cyclic cHAVc1 have the same junction modulatory activities as assessed by in vitro MDCK monolayer model and in situ rat brain perfusion model. In contrast, cyclic cHAVc3 was more effective than linear HAV4 in modulating MDCK cell monolayers and in improving in vivo brain delivery of Gd-DTPA on i.v. administration in Balb/c mice. Cyclic cHAVc3 (t1/2 = 12.95 h) has better plasma stability compared with linear HAV4 (t1/2 = 2.4 h). The duration of the BBB modulation was longer using cHAVc3 (2-4 h) compared with HAV4 (<1 h). Both HAV4 and cHAVc3 peptides also enhanced the in vivo brain delivery of IRdye800cw-PEG (25 kDa) as detected by near IR imaging. The result showed that cyclic cHAVc3 peptide had better activity and plasma stability than linear HAV4 peptide.
authors: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047.
authors: Ahmed
authors: A
authors: Alaofi
authors: Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors: Ngoc
authors: N
authors: On
authors: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047.
authors: Paul
authors: P
authors: Kiptoo
authors: Mass Spectrometry Laboratory, The University of Kansas, Lawrence, Kansas 66047.
authors: Todd D
authors: TD
authors: Williams
authors: Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors: Donald W
authors: DW
authors: Miller
authors: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047. Electronic address: siahaan@ku.edu.
authors: Teruna J
authors: TJ
authors: Siahaan
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004151:Dipeptides / Q000008:administration & dosage / Q000378:metabolism; D004285:Dogs; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014633:Valine / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D004151:Dipeptides; D010456:Peptides, Cyclic; C034124:histidinoalanine; D014633:Valine
keywords: BBB; BBB modulation; HAV peptide; adherens junction; blood-brain barrier; brain delivery; cadherin peptides; paracellular pathway; tight junction