Pharmacokinetics, Toxicity, and Functional Studies of the Selective Kv1.3 Channel Blocker 5-(4-Phenoxybutoxy)Psoralen in Rhesus Macaques

Abstract

The small molecule PAP-1 (5-(4-phenoxybutoxy)psoralen) is a selective blocker of the voltage-gated potassium channel Kv1.3 that is highly expressed in cell membranes of activated effector memory T-cells (TEM). The blockade of Kv1.3 results in membrane depolarization and inhibition of TEM cell proliferation and function. In this study, the in vitro effects of PAP-1 on rhesus macaques (RM) T cells and the in vivo toxicity and pharmacokinetics (PK) were examined in RM with the ultimate aim of utilizing PAP-1 to define the role of TEM in RM infected with simian immunodeficiency virus (SIV). Electrophysiological studies on RM T-cells revealed a Kv1.3 expression pattern similar to that in human T-cells. Thus, PAP-1 effectively suppressed RM TEM cell proliferation. Intravenously administered PAP-1 showed a half-life of 6.4 hrs and the volume of distribution suggested that it is distributed extensively into extravascular compartments. Orally administered PAP-1 was efficiently absorbed and plasma concentrations in RM undergoing a 30-day chronic dosing study indicated that PAP-1 levels that are suppressive to TEM cells in vitro can be achieved and maintained in vivo at a non-toxic dose. PAP-1 selectively inhibited TEM function in vivo as indicated by a modest reactivation of cytomegalovirus (CMV) replication. Immunization of these chronically-treated RM with the live influenza A/PR8 virus suggest that the development of an in vivo flu-specific central memory response was unaffected by PAP-1. These RM remained diseasefree during the entire course of the PAP-1 study. Collectively these data provide a rational basis for future studies with PAP-1 in SIV-infected RM.

Inhibition of the potassium channel Kv1.3 reduces infarction and inflammation in ischemic stroke

“…Yet, our results seem to support this simple therapeutic hypothesis by showing that the observed reduction in infarct area and improvement in neurological deficit following PAP‐1 treatment is accompanied by a reduction in brain levels of IL‐1 β and IFN‐ γ , but not IL‐10 and BDNF or an impairment of phagocytosis. Another attractive feature of using Kv1.3 inhibitors to reduce neuroinflammation in the wake of ischemic stroke is that Kv1.3 inhibitors are known to be immunomodulators rather than immunosuppressants and do not impair the ability of rodents to clear acute infections or of primates to develop vaccine responses 5, 8. Kv1.3 inhibitors are therefore unlikely to further increase the risk of respiratory and urinary tract infections, which are responsible for considerable morbidity and mortality after stroke 45, 49.…”

“…In addition, K V 1.3 blockade seems to be relatively safe and well tolerated. Toxicity studies with PAP‐1 and the peptidic K V 1.3 blocker ShK‐186 have so far not revealed any toxicity despite 6 months or 28 days of continuous administration in rats or rhesus macaques 4, 8. PAP‐1 has further completed IND‐enabling toxicity studies, while ShK‐186 has passed both IND toxicity studies and Phase‐1 safety studies without any adverse findings 6, 9…”

“…As Kv1.3 blockers preferentially target T EM cells, Kv1.3 blockers do not impair the ability to clear acute infections or develop vaccine responses. For example, Kv1.3 blockers do not affect the ability of rats to clear influenza virus and Chlamydia trachomatis 5 or prevent rhesus macaques from developing protective, flu‐specific central memory T‐cell responses following immunization with a live influenza vaccine 8. Based on these encouraging target validation studies, ShK‐186, now called Dalazatide, was moved into clinical trials, where it exhibited no major safety findings in Phase‐1a and showed efficacy in Phase‐1b studies in plaque psoriasis and is now being developed further 9…”

“…PAP‐1 is currently the most potent and selective small molecule Kv1.3 blocker available. It inhibits Kv1.3 with an IC 50 of 2 nmol/L,22 has a half‐life of 3 h in rodents, is orally available, brain penetrant and does not exhibit any long‐term toxicity in rodents or primates 4, 8, 23…”

Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

“…Despite the multiorgan effects of ShK-186, the peptide has an excellent safety profile in rodents and nonhuman primates following repeat-dose administration for a month (15)(16)(17)(18)(19)(20). PAP-1, another Kv1.3 blocker, is also well tolerated by monkeys and rats administered the compound once daily for 1 and 6 mo, respectively (20,74). Due to its selective immunomodulatory action on T EM cells, ShK-186 is not a generalized immunosuppressant and hence does not compromise the protective immune response to acute viral and bacterial infections (17,18).…”