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 BBB modulatory activity and plasma stability of HAV peptides, which are derived from the EC1 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 upon i.v. administration in Balb/c mice. Cyclic cHAVc3 (t1/2 = 12.95 h) has better plasma stability compared to linear HAV4 (t1/2 = 2.4 h). The duration of the BBB modulation was longer using cHAVc3 (2–4 h) compared to 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.

Crystal Structure of Human E-Cadherin-EC1EC2 in Complex with a Peptidomimetic Competitive Inhibitor of Cadherin Homophilic Interaction

“…Moreover, effective and selective cell-cell junctions modulator peptides may represent potential pharmaceutical excipients to improve drug delivery across biological barriers. 37,38 EXPERIMENTAL SECTION…”

Brain Delivery of Drug and MRI Contrast Agent: Detection and Quantitative Determination of Brain Deposition of CPT-Glu Using LC–MS/MS and Gd-DTPA Using Magnetic Resonance Imaging

“…12 For a large molecule such as IRdye-labeled 25 kDa polyethylene glycol (IRdye 800cw-PEG), both linear HAV6 and cyclic cHAVc3 peptides increase its brain delivery when administered together with peptide. 12, 41 However, when the IRdye 800cw-PEG was delivered 1 h after administration of linear HAV6 or cyclic cHAVc3 peptides there was no enhancement of brain delivery. 12, 41 In other words, large molecules could be only be delivered at the early state of the BBB modulation.…”

“…12, 41 However, when the IRdye 800cw-PEG was delivered 1 h after administration of linear HAV6 or cyclic cHAVc3 peptides there was no enhancement of brain delivery. 12, 41 In other words, large molecules could be only be delivered at the early state of the BBB modulation. This result suggests that the BBB size of opening by cadherin peptides is a time-dependent manner and the opening for small molecules has a longer time window than for large molecules.…”

Probing the interaction between cHAVc3 peptide and the EC1 domain of E-cadherin using NMR and molecular dynamics simulations

“…The linear peptide was cleaved from the resin and purified by reversed-phase HPLC using a C18 column. The cyclization reaction was done by bubbling air into a dilute solution of peptide in sodium bicarbonate buffer at pH 8.5 as previously described (Alaofi et al , 2015). The peptide was purified with semi-preparative HPLC using a C18 column.…”

“…administration (Kiptoo et al , 2011; On et al , 2014). Recently, the cyclic cHAVc3 peptide (cyclo-(1,6)Ac-CSHAVC-NH 2 ) was shown to have better activity than linear HAV4 peptide (Ac-SHAVAS-NH 2 ) in modulating the intercellular junctions of MDCK cell monolayers and in enhancing in vivo brain delivery of Gd-DTPA in Balb/c mice (Alaofi et al , 2015). In addition, cyclic cHAVc3 has better plasma stability than the linear HAV4 peptide (Alaofi et al , 2015).…”