TY - JOUR
T1 - Synthesis and Characterization of Long-Acting Darunavir Prodrugs
AU - Banoub, Mary G.
AU - Bade, Aditya N.
AU - Lin, Zhiyi
AU - Cobb, Denise
AU - Gautam, Nagsen
AU - Dyavar Shetty, Bhagya Laxmi
AU - Wojtkiewicz, Melinda
AU - Alnouti, Yazen
AU - McMillan, Joellyn
AU - Gendelman, Howard E.
AU - Edagwa, Benson
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2020/1/6
Y1 - 2020/1/6
N2 - Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains unattainable. This is complicated by adverse side effects and poor adherence to lifelong therapy leading to the emergence of viral drug resistance. Thus, there is an immediate need for cellular and tissue-targeted long-acting (LA) ART formulations. Herein, we describe two LA prodrug formulations of darunavir (DRV), a potent antiretroviral protease inhibitor. Two classes of DRV prodrugs, M1DRV and M2DRV, were synthesized as lipophilic and hydrophobic prodrugs and stabilized into aqueous suspensions designated NM1DRV and NM2DRV. The formulations demonstrated enhanced intracellular prodrug levels with sustained drug retention and antiretroviral activities for 15 and 30 days compared to native DRV formulation in human monocyte-derived macrophages. Pharmacokinetics tests of NM1DRV and NM2DRV administered to mice demonstrated sustained drug levels in blood and tissues for 30 days. These data, taken together, support the idea that LA DRV with sustained antiretroviral responses through prodrug nanoformulations is achievable.
AB - Antiretroviral therapy (ART) has improved the quality of life in patients infected with HIV-1. However, complete viral suppression within anatomical compartments remains unattainable. This is complicated by adverse side effects and poor adherence to lifelong therapy leading to the emergence of viral drug resistance. Thus, there is an immediate need for cellular and tissue-targeted long-acting (LA) ART formulations. Herein, we describe two LA prodrug formulations of darunavir (DRV), a potent antiretroviral protease inhibitor. Two classes of DRV prodrugs, M1DRV and M2DRV, were synthesized as lipophilic and hydrophobic prodrugs and stabilized into aqueous suspensions designated NM1DRV and NM2DRV. The formulations demonstrated enhanced intracellular prodrug levels with sustained drug retention and antiretroviral activities for 15 and 30 days compared to native DRV formulation in human monocyte-derived macrophages. Pharmacokinetics tests of NM1DRV and NM2DRV administered to mice demonstrated sustained drug levels in blood and tissues for 30 days. These data, taken together, support the idea that LA DRV with sustained antiretroviral responses through prodrug nanoformulations is achievable.
KW - LASER ART
KW - darunavir
KW - long acting
KW - prodrugs
KW - protease inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85076251311&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076251311&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.9b00871
DO - 10.1021/acs.molpharmaceut.9b00871
M3 - Article
C2 - 31742407
AN - SCOPUS:85076251311
SN - 1543-8384
VL - 17
SP - 155
EP - 166
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 1
ER -