Diseases of the central nervous system such as schizophrenia, meningitis, migraine, Parkinson's and Alzheimer's disease, along with other neurological disorders, such as addiction, require delivery of the drug to the brain for effective treatment. However, treatment for these diseases is still a challenge due to the inability of many drugs, especially hydrophobic and large molecular weight drugs such as peptides and proteins, to cross the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB). Direct delivery of therapeutic agents from the nasal cavity into the brain bypasses the BBB and BCB and offers a viable alternative to conventional strategies for brain targeting, but remains a major challenge due to the lack of efficient delivery system. To increase intranasal delivery of therapeutic peptides to the brain we designed a novel strategy based on grafting a bioactive amino acid sequence onto the scaffold of cyclic peptide odorranalectin (OL) that exhibits lectin-like properties. OL can specifically bind to L-fucose, which is widely distributed on the olfactory epithelium of nasal mucosa, suggesting a possibility for extending its residence time in the nasal cavity, thereby allowing its increased adsorption. As a proof-of-concept, we have successfully synthesized a novel cyclic opioid peptide DADLE-OL by grafting the sequence of a known mixed ??and ??agonist, [D-Ala2, D-Leu5] enkephalin (DADLE), into the OL scaffold. In our piot studies we have demonstrated that DADLE-OL can be delivered via the nasal route to the mouse brain and that this novel opioid peptide can produce biological effects following the intranasal administration in mice. To further validate our approach we propose to: (a) prepare a focused positional scanning combinatorial library (PSCL) based on the OL scaffold (Aim 1), (b) screen the prepared PSCL for affinity toward ?????and???opioid receptors as model trgets for the treatment of brain disorders and assess the most selective and potent analogs abilities to bind L-fucose for bio-adhesive purpose (Aim 2), and (c) assess the selected OL analogs ability to be transported from nose-to-brain in a mouse model and produce biological effects (Aim 3). The information gained from the proposed research will assist us in establishing the lead structure for further modification and development of novel therapeutic agents for the treatment of CNS diseases.
Treatment of central nervous system diseases is challenging due to the inability of many therapeutic agents, especially hydrophobic and large molecular weight drugs such as peptides and proteins, to cross the blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCB) barrier. Alternatively, intranasal administration may enable these therapeutic agents to directly enter the brain by bypassing the BBB and BCB. To increase intranasal delivery of therapeutic peptides to the brain, we designed a novel strategy based on grafting a bioactive sequence into the carrier cyclic peptide scaffold that exhibits bio-adhesive properties.
| Rodriguez, Maria C; Yongye, Austin B; Cudic, Mihael et al. (2017) Targeting cancer-specific glycans by cyclic peptide lectinomimics. Amino Acids 49:1867-1883 |
