ArticleProceedings of the National Academy of Sciences of the United States of America2009
FK506-binding protein (FKBP) partitions a modified HIV protease inhibitor into blood cells and prolongs its lifetime in vivo.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 35 citations in OpenAlex.
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- Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays.Angewandte Chemie (International ed. in English) · 2019Article
- Rapamycin-inspired macrocycles with new target specificity.Nature chemistry · 2019Article
- Chemically induced proximity in biology and medicine.Science (New York, N.Y.) · 2018Review
- Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds.Journal of medicinal chemistry · 2016Review
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- Selective Targeting of Cells via Bispecific Molecules That Exploit Coexpression of Two Intracellular Proteins.ACS chemical biology · 2015Article
- Bifunctional ligands allow deliberate extrinsic reprogramming of the glucocorticoid receptor.Molecular endocrinology (Baltimore, Md.) · 2014Article
- Adamantyl derivative as a potent inhibitor of Plasmodium FK506 binding protein 35.ACS medicinal chemistry letters · 2013Article
- Creating diverse target-binding surfaces on FKBP12: synthesis and evaluation of a rapamycin analogue library.ACS combinatorial science · 2011Article
- Chemoselective small molecules that covalently modify one lysine in a non-enzyme protein in plasma.Nature chemical biology · 2010Article
- Synthesis of orthogonally reactive FK506 derivatives via olefin cross metathesis.Bioorganic & medicinal chemistry · 2009Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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