Synthesis and Characterization of Long-Acting Darunavir Prodrugs

Mary G. Banoub, Aditya N. Bade, Zhiyi Lin, Denise Cobb, Nagsen Gautam, Bhagya Laxmi Dyavar Shetty, Melinda Wojtkiewicz, Yazen Alnouti, Joellyn McMillan, Howard E. Gendelman, Benson Edagwa

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)155-166
Number of pages12
JournalMolecular Pharmaceutics
Volume17
Issue number1
DOIs
StatePublished - Jan 6 2020

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Prodrugs
Viral Drug Resistance
Protease Inhibitors
Pharmaceutical Preparations
HIV-1
Suspensions
Therapeutics
Pharmacokinetics
Macrophages
Quality of Life
Darunavir

Keywords

  • LASER ART
  • darunavir
  • long acting
  • prodrugs
  • protease inhibitors

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Banoub, M. G., Bade, A. N., Lin, Z., Cobb, D., Gautam, N., Dyavar Shetty, B. L., ... Edagwa, B. (2020). Synthesis and Characterization of Long-Acting Darunavir Prodrugs. Molecular Pharmaceutics, 17(1), 155-166. https://doi.org/10.1021/acs.molpharmaceut.9b00871

Synthesis and Characterization of Long-Acting Darunavir Prodrugs. / Banoub, Mary G.; Bade, Aditya N.; Lin, Zhiyi; Cobb, Denise; Gautam, Nagsen; Dyavar Shetty, Bhagya Laxmi; Wojtkiewicz, Melinda; Alnouti, Yazen; McMillan, Joellyn; Gendelman, Howard E.; Edagwa, Benson.

In: Molecular Pharmaceutics, Vol. 17, No. 1, 06.01.2020, p. 155-166.

Research output: Contribution to journalArticle

Banoub, MG, Bade, AN, Lin, Z, Cobb, D, Gautam, N, Dyavar Shetty, BL, Wojtkiewicz, M, Alnouti, Y, McMillan, J, Gendelman, HE & Edagwa, B 2020, 'Synthesis and Characterization of Long-Acting Darunavir Prodrugs', Molecular Pharmaceutics, vol. 17, no. 1, pp. 155-166. https://doi.org/10.1021/acs.molpharmaceut.9b00871
Banoub MG, Bade AN, Lin Z, Cobb D, Gautam N, Dyavar Shetty BL et al. Synthesis and Characterization of Long-Acting Darunavir Prodrugs. Molecular Pharmaceutics. 2020 Jan 6;17(1):155-166. https://doi.org/10.1021/acs.molpharmaceut.9b00871
Banoub, Mary G. ; Bade, Aditya N. ; Lin, Zhiyi ; Cobb, Denise ; Gautam, Nagsen ; Dyavar Shetty, Bhagya Laxmi ; Wojtkiewicz, Melinda ; Alnouti, Yazen ; McMillan, Joellyn ; Gendelman, Howard E. ; Edagwa, Benson. / Synthesis and Characterization of Long-Acting Darunavir Prodrugs. In: Molecular Pharmaceutics. 2020 ; Vol. 17, No. 1. pp. 155-166.
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