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 S Ciborowski, Val S. Goodfellow, Tadeusz A Wysocki, Beata J. Wysocki, Larisa Y Poluektova, Xin Ming Liu, JoEllyn M McMillan, Santhi Gorantla, Harris A. Gelbard, Howard Eliot Gendelman

Research output: Contribution to journalArticle

18 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

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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

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. S., Goodfellow, V. S., Wysocki, T. A., Wysocki, B. J., Poluektova, L. Y., Liu, X. M., McMillan, J. 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