Octadecyloxyethyl benzyl tenofovir: A novel tenofovir diester provides sustained intracellular levels of tenofovir diphosphate.
Antiviral Res
; 171: 104614, 2019 11.
Article
en En
| MEDLINE
| ID: mdl-31550449
ABSTRACT
Pre-exposure prophylaxis (PrEP) with topically or systemically administered antiretroviral agents can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials using tenofovir-containing agents, HIV-1 acquisition is reduced but not eliminated. Incomplete adherence remains the major contributor to failure. Sustained release or long-acting antiretroviral agents may provide better HIV-1 protection by reducing the clinical impact of incomplete adherence. To reduce dosing frequency, we synthesized a novel tenofovir prodrug, octadecyloxyethyl benzyl tenofovir (ODE-Bn-TFV), that is designed to release TFV slowly in tissues, and showed potent anti-HIV activity in vitro (EC50â¯=â¯1.7â¯nM). In cells exposed to 14C labeled TFV, ODE-Bn-TFV or the quickly activated monoester ODE-TFV, rapid cellular uptake for both lipophilic analogs was noted, achieving 50-fold higher levels than unmodified TFV after 48â¯h. Following exposure to ODE-[8-14C]TFV, the intracellular diphosphate levels were approximately four-fold higher than with ODE-Bn-TFV. However, intracellular TFVpp drug levels fell rapidly yielding a half-life of about two days. TFVpp levels in ODE-Bn-TFV treated cells decreased much more slowly and reached half-maximal levels in about seven days. These results suggest early accumulation of ODE-Bn-TFV followed by sustained intracellular release following cleavage of the ester bonds linking the ODE and benzyl moieties to the active molecular precursor, thereby potentially allowing for less frequent administration than with more rapidly activated forms of tenofovir.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tenofovir
Límite:
Humans
Idioma:
En
Revista:
Antiviral Res
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos