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

Gang Zhang, Dongwei Guo, Prasanta K. Dash, Mariluz Araínga, Jayme L. Wiederin, Nicole A. Haverland, Jaclyn Knibbe-Hollinger, Andrea Martinez-Skinner, Pawel Ciborowski, Val S. Goodfellow, Tadeusz A. Wysocki, Beata J. Wysocki, Larisa Y. Poluektova, Xin Ming Liu, Jo Ellyn M. McMillan, Santhi Gorantla, Harris A. Gelbard, Howard E. Gendelman

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)109-122
Number of pages14
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2016

Keywords

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

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

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  • Cite this

    Zhang, G., Guo, D., Dash, P. K., Araínga, M., Wiederin, J. L., Haverland, N. A., Knibbe-Hollinger, J., Martinez-Skinner, A., Ciborowski, P., Goodfellow, V. S., Wysocki, T. A., Wysocki, B. J., Poluektova, L. Y., Liu, X. M., McMillan, J. E. M., Gorantla, S., Gelbard, H. A., & Gendelman, H. E. (2016). The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine: Nanotechnology, Biology, and Medicine, 12(1), 109-122. https://doi.org/10.1016/j.nano.2015.09.009