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

17 Citations (Scopus)

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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T-cells
Recycling
Tissue
Crystalline materials
Pharmaceutical Preparations
Half-Life
HIV-1
HIV Reverse Transcriptase
Ritonavir
Neuroprotective Agents
Drug Combinations
Therapeutics
Endosomes
Antiviral Agents
Lymphoid Tissue
Marriage
Viral Load
Proteomics
HIV Infections
URMC-099

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

The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. / Zhang, Gang; Guo, Dongwei; Dash, Prasanta K.; Araínga, Mariluz; Wiederin, Jayme L.; Haverland, Nicole A.; Knibbe-Hollinger, Jaclyn; Martinez-Skinner, Andrea; Ciborowski, Pawel S; Goodfellow, Val S.; Wysocki, Tadeusz A; Wysocki, Beata J.; Poluektova, Larisa Y; Liu, Xin Ming; McMillan, JoEllyn M; Gorantla, Santhi; Gelbard, Harris A.; Gendelman, Howard Eliot.

In: Nanomedicine: Nanotechnology, Biology, and Medicine, Vol. 12, No. 1, 01.01.2016, p. 109-122.

Research output: Contribution to journalArticle

Zhang, G, Guo, D, Dash, PK, Araínga, M, Wiederin, JL, Haverland, NA, Knibbe-Hollinger, J, Martinez-Skinner, A, Ciborowski, PS, Goodfellow, VS, Wysocki, TA, Wysocki, BJ, Poluektova, LY, Liu, XM, McMillan, JM, Gorantla, S, Gelbard, HA & Gendelman, HE 2016, 'The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy', Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 12, no. 1, pp. 109-122. https://doi.org/10.1016/j.nano.2015.09.009
Zhang, Gang ; Guo, Dongwei ; Dash, Prasanta K. ; Araínga, Mariluz ; Wiederin, Jayme L. ; Haverland, Nicole A. ; Knibbe-Hollinger, Jaclyn ; Martinez-Skinner, Andrea ; Ciborowski, Pawel S ; Goodfellow, Val S. ; Wysocki, Tadeusz A ; Wysocki, Beata J. ; Poluektova, Larisa Y ; Liu, Xin Ming ; McMillan, JoEllyn M ; Gorantla, Santhi ; Gelbard, Harris A. ; Gendelman, Howard Eliot. / The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. In: Nanomedicine: Nanotechnology, Biology, and Medicine. 2016 ; Vol. 12, No. 1. pp. 109-122.
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