Small Therapeutic Peptides: In vitro pharmacokinetics of alpha-carboxyl terminus 11 peptide in rat plasma
| dc.contributor.author | Tasdemiroglu, Yagmur | en |
| dc.contributor.committeechair | He, Jia-Qiang | en |
| dc.contributor.committeechair | Gourdie, Robert G. | en |
| dc.contributor.committeemember | Ehrich, Marion F. | en |
| dc.contributor.committeemember | Davis, Jennifer Lynn | en |
| dc.contributor.department | Biomedical and Veterinary Sciences | en |
| dc.date.accessioned | 2021-06-05T08:03:34Z | en |
| dc.date.available | 2021-06-05T08:03:34Z | en |
| dc.date.issued | 2021-06-04 | en |
| dc.description.abstract | Cardiovascular diseases affect one third of the U.S. population and are the number one cause of death globally. Acute myocardial infarction is one of the most catastrophic cardiovascular diseases that permanently alters patient's lives. Small molecule drugs, surgery, medical devices and lifestyle changes are the current treatment methods that only address symptoms and fail to cure cardiovascular disorders. Small therapeutic peptides are emerging methods to treat diseases ranging from cancer to auto-immune disorders. Due to their nature, they are non-toxic, non-immunogenic, biocompatible and highly target specific. However, because of their small size and lack of tertiary structure, they have a very short half-life. Alpha-carboxyl terminus 11 peptide (αCT11) is a 9 amino acid long small peptide that has shown to promote left ventricular function recovery when mouse hearts are perfused with the peptide prior to an ischemia-reperfusion injury. This study investigates the in vitro pharmacokinetics of αCT11 in rat plasma in the presence of protease and phosphatase inhibitor cocktails to provide a method to delay its degradation and to understand the degradation pattern of the peptide in vitro. The effect of time, temperature, presence of inhibitors and sex are investigated. Results have shown that while sex does not have a significant effect on αCT11 degradation, time and temperature significantly promote its degradation. Utilization of inhibitors also leads to a pronounced delay in αCT11 degradation, as the amount of αCT11 remaining in plasma increases from almost undetectable to 15-16% upon introduction of inhibitors. These results indicate that αCT11 degradation can be delayed significantly when inhibitor cocktails are used, bringing αCT11 closer to being used in a clinical setting to address ischemia-reperfusion injuries. | en |
| dc.description.abstractgeneral | Cardiovascular diseases affect millions of people worldwide and they are the number one cause of death globally. Current treatments for cardiovascular diseases mainly focus on alleviating symptoms as they arise and delaying the disease progression using small molecule drugs and lifestyle changes, which unfortunately are unable to cure the diseases permanently. Peptide treatment is a novel method to address various traditionally incurable diseases, such as auto-immune disorders and cancer. These therapeutic peptides are highly target specific, typically non-toxic and highly biocompatible since they are designed based on native proteins. Even though small therapeutic peptides have numerous benefits, a major drawback is that they have a very short half-life in plasma. Alpha-carboxyl terminus 11 peptide (αCT11) is a small peptide derived from alpha-carboxyl terminus 1 peptide (αCT1), which is in phase 2 clinical trials for chronic wound healing. It has been shown that αCT11 has cardioprotective effects when the heart is perfused with the peptide before an ischemia-reperfusion injury, such as a heart attack. This study investigates the in vitro pharmacokinetic properties of αCT11 in rat plasma with respect to time, temperature and sex with the aim to provide an effective method to allow αCT11 to remain in plasma for a longer period of time. As a method to delay αCT11 degradation due to plasma enzymes, enzyme inhibitors are used, which delayed the αCT11 breakdown significantly. The results have also shown that time and temperature are the main factors affecting αCT11 degradation in rat plasma in vitro while sex is not a significant factor. These results indicate that this small peptide can be protected in plasma with the use of inhibitors. This discovery can be a stepping stone to use αCT11 in clinical settings to help treat cardiovascular diseases. | en |
| dc.description.degree | Master of Science | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:31343 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/103639 | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | Small Therapeutic Peptide | en |
| dc.subject | Pharmacokinetics | en |
| dc.subject | Alpha-Carboxyl Terminus 11 | en |
| dc.title | Small Therapeutic Peptides: In vitro pharmacokinetics of alpha-carboxyl terminus 11 peptide in rat plasma | en |
| dc.type | Thesis | en |
| thesis.degree.discipline | Biomedical and Veterinary Sciences | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | masters | en |
| thesis.degree.name | Master of Science | en |