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

详细信息    查看全文

• 作者：Gang Zhang ; PhD^a ; ¹ ; Dongwei Guo ; MS^a ; ^b ; ¹ ; Prasanta K. Dash ; PhD^a ; ¹ ; Mariluz Araí ; nga ; DVM ; MSc ; PhD^a ; Jayme L. Wiederin ; MS^a ; ^c ; Nicole A. Haverland ; PhD^a ; ² ; Jaclyn Knibbe-Hollinger ; MPH^a ; Andrea Martinez-Skinner ; PhD^a ; Pawel Ciborowski ; PhD^a ; Val S. Goodfellow ; PhD^d ; Tadeusz A. Wysocki ; PhD^e ; Beata J. Wysocki ; PhD^e ; Larisa Y. Poluektova ; MD ; PhD^a ; Xin-Ming Liu ; PhD^a ; ^b ; ³ ; JoEllyn M. McMillan ; PhD^a ; Santhi Gorantla ; PhD^a ; Harris A. Gelbard ; MD ; PhD^f ; Howard E. Gendelman ; MD^a ; ^b ; ^{hegendel@unmc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HIV-1 ; Long-acting nanoformulations ; URMC-099 ; Humanized mice ; Phagolysosome ; Rab proteins
• 刊名：Nanomedicine: Nanotechnology, Biology and Medicine
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：12
• 期：1
• 页码：109-122
• 全文大小：3988 K

文摘

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.