title: FK506-binding protein (FKBP) partitions a modified HIV protease inhibitor into blood cells and prolongs its lifetime in vivo.
abstract: HIV protease inhibitors are a key component of anti-retroviral therapy, but their susceptibility to cytochrome P(450) 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 (IC(50) = 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.
authors.affiliation: Department of Pathology and the Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Marinec
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Barr
authors.forename: Mitchell W
authors.initials: MW
authors.lastname: Mutz
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Crabtree
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
mesh_terms: D000818:Animals; D002460:Cell Line; D004912:Erythrocytes / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D006678:HIV / Q000187:drug effects / Q000472:pathogenicity; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022021:Tacrolimus Binding Proteins / Q000502:physiology*
chemical_list: D017320:HIV Protease Inhibitors; D022021:Tacrolimus Binding Proteins