title: The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy.
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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Prasanta K
authors.initials: PK
authors.lastname: Dash
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Mariluz
authors.initials: M
authors.lastname: Araínga
authors.affiliation: 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.
authors.forename: Jayme L
authors.initials: JL
authors.lastname: Wiederin
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Haverland
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Knibbe-Hollinger
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Martinez-Skinner
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Ciborowski
authors.affiliation: Califia Bio, San Diego, CA, USA.
authors.forename: Val S
authors.initials: VS
authors.lastname: Goodfellow
authors.affiliation: Department of Computer and Electronics Engineering, University of Nebraska-Lincoln, Omaha, NE, USA.
authors.forename: Tadeusz A
authors.initials: TA
authors.lastname: Wysocki
authors.affiliation: Department of Computer and Electronics Engineering, University of Nebraska-Lincoln, Omaha, NE, USA.
authors.forename: Beata J
authors.initials: BJ
authors.lastname: Wysocki
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Larisa Y
authors.initials: LY
authors.lastname: Poluektova
authors.affiliation: 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.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: JoEllyn M
authors.initials: JM
authors.lastname: McMillan
authors.affiliation: Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.affiliation: Department of Neurology, Center for Neural Development & Disease, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Harris A
authors.initials: HA
authors.lastname: Gelbard
authors.affiliation: 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.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D000069446:Atazanavir Sulfate / Q000008:administration & dosage*; D004359:Drug Therapy, Combination / Q000379:methods; D015658:HIV Infections / Q000175:diagnosis / Q000517:prevention & control* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D016513:Mice, SCID; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D016896:Treatment Outcome; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D044966:Anti-Retroviral Agents; D000069446:Atazanavir Sulfate; D020930:MAP Kinase Kinase Kinases; D053769:Nanocapsules; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C583037:URMC-099
keywords: HIV-1; Humanized mice; Long-acting nanoformulations; Phagolysosome; Rab proteins; URMC-099