FK506-binding protein (FKBP) partitions a modified HIV protease inhibitor into blood cells and prolongs its lifetime in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 5; pp. 1336 - 1341
• Main Authors: Marinec, Paul S, Chen, Lei, Barr, Kenneth J, Mutz, Mitchell W, Crabtree, Gerald R, Gestwicki, Jason E
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.02.2009; National Acad Sciences
• Subjects: Animals; Antivirals; Binding sites; Biochemistry; Biological Sciences; Blood; Blood plasma; Cell Line; Erythrocytes - metabolism; Fluorescence Resonance Energy Transfer; Half-Life; HIV; HIV - drug effects; HIV - pathogenicity; HIV 1; HIV protease inhibitors; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - pharmacokinetics; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Inhibitory concentration 50; Lymphocytes - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; Molecules; Physical Sciences; Prodrugs; Protease inhibitors; Proteases; Proteins; Tacrolimus Binding Proteins - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0805375106

HIV protease inhibitors are a key component of anti-retroviral therapy, but their susceptibility to cytochrome P₄₅₀ metabolism reduces their systemic availability and necessitates repetitive dosing. Importantly, failure to maintain adequate inhibitor levels is believed to provide an opportunity for resistance to emerge; thus, new strategies to prolong the lifetime of these drugs are needed. Toward this goal, numerous prodrug approaches have been developed, but these methods involve creating inactive precursors that require enzymatic processing. Using an alternative strategy inspired by the natural product FK506, we have synthetically modified an HIV protease inhibitor such that it acquires high affinity for the abundant, cytoplasmic chaperone, FK506-binding protein (FKBP). This modified protease inhibitor maintains activity against HIV-1 protease (IC₅₀ = 19 nM) and, additionally, it is partitioned into the cellular component of whole blood via binding to FKBP. Interestingly, redistribution into this protected niche reduces metabolism and improves its half-life in mice by almost 20-fold compared with the unmodified compound. Based on these findings, we propose that addition of FKBP-binding groups might partially overcome the poor pharmacokinetic properties of existing HIV protease inhibitors and, potentially, other drug classes.