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TAT-Modified ω-Conotoxin MVIIA for Crossing the Blood-Brain Barrier
- Source :
- Marine Drugs, Volume 17, Issue 5, Marine Drugs, Vol 17, Iss 5, p 286 (2019)
- Publication Year :
- 2019
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2019.
-
Abstract
- As the first in a new class of non-opioid drugs, &omega<br />Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA&rsquo<br />s ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.
- Subjects :
- Male
Recombinant Fusion Proteins
Central nervous system
Analgesic
Pain
Pharmaceutical Science
Pharmacology
Blood–brain barrier
Article
omega-Conotoxins
Mice
03 medical and health sciences
0302 clinical medicine
In vivo
Tremor
Drug Discovery
medicine
Animals
Conotoxin
lcsh:QH301-705.5
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Pain Measurement
030304 developmental biology
0303 health sciences
Ziconotide
business.industry
ziconotide
Calcium Channel Blockers
peptide
TAT (the transactivator of transcription domain)
medicine.anatomical_structure
lcsh:Biology (General)
Opioid
Blood-Brain Barrier
BBB (blood-brain barrier) penetration
analgesics
RNA-Binding Protein FUS
Female
tat Gene Products, Human Immunodeficiency Virus
Nasal administration
Peptides
business
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Marine Drugs, Volume 17, Issue 5, Marine Drugs, Vol 17, Iss 5, p 286 (2019)
- Accession number :
- edsair.doi.dedup.....5ce87439c5c4bb12ec575d8ec916a002
- Full Text :
- https://doi.org/10.14288/1.0379168