Biological evaluation of a phosphate ester prodrug of 10-methyl-aplog-1, a simplified analogue of aplysiatoxin, as a possible latency-reversing agent for HIV reactivation.

10-Methyl-aplog-1 (10MA-1), a simplified analogue of aplysiatoxin, exhibits a high binding affinity for protein kinase C (PKC) isozymes with minimal tumor-promoting and proinflammatory activities. A recent study suggests that 10MA-1 could reactivate latent human immunodeficiency virus (HIV) in vitro for HIV eradication strategy. However, further in vivo studies were abandoned by a dose limit caused by the minimal water solubility of 10MA-1. To overcome this problem, we synthesized a phosphate ester of 10MA-1, 18-O-phospho-10-methyl-aplog-1 (phos-10MA-1) to improve water solubility for in vivo studies. The solubility, PKC binding affinity, and biological activity of phos-10MA-1 were examined in vitro, and the biological activity was comparable with 10MA-1. The pharmacokinetics studies in vivo were also examined and suggest that further optimization for improving metabolic stability is required in the future.