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Nanomedicine. 2016 Jan;12(1):109-22. doi: 10.1016/j.nano.2015.09.009. Epub 2015 Oct 22.

The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy.

Author information

1
Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
2
Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
3
Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA; Office of the Vice Chancellor for Research, University of Nebraska Medical Center, Omaha, NE, USA.
4
Califia Bio, San Diego, CA, USA.
5
Department of Computer and Electronics Engineering, University of Nebraska-Lincoln, Omaha, NE, USA.
6
Department of Neurology, Center for Neural Development & Disease, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, USA.
7
Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: hegendel@unmc.edu.

Abstract

During studies to extend the half-life of crystalline nanoformulated antiretroviral therapy (nanoART) the mixed lineage kinase-3 inhibitor URMC-099, developed as an adjunctive neuroprotective agent was shown to facilitate antiviral responses. Long-acting ritonavir-boosted atazanavir (nanoATV/r) nanoformulations co-administered with URMC-099 reduced viral load and the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues more than either drug alone in infected humanized NOD/SCID/IL2Rγc-/- mice. The drug effects were associated with sustained ART depots. Proteomics analyses demonstrated that the antiretroviral responses were linked to affected phagolysosomal storage pathways leading to sequestration of nanoATV/r in Rab-associated recycling and late endosomes; sites associated with viral maturation. URMC-099 administered with nanoATV induced a dose-dependent reduction in HIV-1p24 and reverse transcriptase activity. This drug combination offers a unique chemical marriage for cell-based viral clearance. From the Clinical Editor: Although successful in combating HIV-1 infection, the next improvement in antiretroviral therapy (nanoART) would be to devise long acting therapy, such as intra-cellular depots. In this report, the authors described the use of nanoformulated antiretroviral therapy given together with the mixed lineage kinase-3 inhibitor URMC-099, and showed that this combination not only prolonged drug half-life, but also had better efficacy. The findings are hoped to be translated into the clinical setting in the future.

KEYWORDS:

HIV-1; Humanized mice; Long-acting nanoformulations; Phagolysosome; Rab proteins; URMC-099

PMID:
26472049
PMCID:
PMC4728028
DOI:
10.1016/j.nano.2015.09.009
[Indexed for MEDLINE]
Free PMC Article

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