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

G Zhang, D Guo, PK Dash, M Araínga… - … , Biology and Medicine, 2016 - Elsevier
G Zhang, D Guo, PK Dash, M Araínga, JL Wiederin, NA Haverland, J Knibbe-Hollinger…
Nanomedicine: Nanotechnology, Biology and Medicine, 2016Elsevier
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 …
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.
Elsevier