Distribution of KAI-9803, a Novel δ-Protein Kinase C Inhibitor, after Intravenous Administration to Rats

Abstract

ABSTRACT:KAI-9803 is composed of a selective ␦-protein kinase C (␦PKC) inhibitor peptide derived from the ␦V1-1 portion of ␦PKC (termed "cargo peptide"), conjugated reversibly to the cell-penetrating peptide 11-amino acid, arginine-rich sequence of the HIV type 1 transactivator protein (TAT 47-57 ; termed "carrier peptide") via a disulfide bond. KAI-9803 administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. In the study presented here, we examined the TAT 47-57 -mediated distribution of KAI-9803 in rats after a single intravenous bolus administration (1 mg/kg).14 C-KAI-9803 was rapidly delivered to many tissues, including the heart (1.21 g eq/g tissue), while being quickly cleared from the systemic circulation.

Novel Drp1 inhibitor diminishes aberrant mitochondrial fission and neurotoxicity

“…It is a conjugate between the Drp1-dervied sequence in region 110 (cargo) and the cell-permeable peptide carrier TAT 47-57 , which has been widely used for cargo delivery in cultures and in vivo. Our previous studies showed that TAT-conjugated peptides can quickly enter cells and pass through the blood-brain barrier (Bright et al, 2004;Qi et al, 2008) and have extensive bio-distribution within minutes after single dose treatment in vivo and in cultures (Begley et al, 2004;Miyaji et al, 2011). Thus, P110 may be useful in treatment of diseases associated with excessive mitochondrial fission, such as Parkinsonism.…”

Cell-penetrating peptides: strategies for anticancer treatment

“…Despite the large number of preclinical and clinical trials that have been conducted (or are currently underway), no CPP or CPP conjugate has gained US Food and Drug Administration (FDA) approval as a cancer therapeutic. The CPP conjugate cyclosporinoctaarginine (PsorBan, by CellGate Inc.) has been used for topical therapy in psoriasis [80], and CPPs have also been used to treat wrinkles [81], minimize fibrosis or scarring [82], in myocardial infarction and spinal cord injury [83,84], inflammation [83,84], and many other therapeutic applications. A few clinical trials are currently underway that use CPPs for cancer therapy.…”

Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells

“…The conjugate entered Phase II clinical trial, which was eventually terminated in 2003. The modern CPP-vaccines were tested for myocardial infarction [92], spinal cord injury [93] and HIV vaccination. Other studies have been re performed in metastatic solid tumors [89] or in acute sensorineural hearing loss caused by cochlear injury [94].…”