Clouser Christine L, Bonnac Laurent, Mansky Louis M, Patterson Steven E
Institute for Molecular Virology, University of Minnesota, Minneapolis, MN, USA.
Antivir Chem Chemother. 2014 Dec 16;23(6):223-30. doi: 10.3851/IMP2682.
Over 25 drugs have been approved for the treatment of HIV-1 replication. All but one of these drugs is delivered as an oral medication. Previous studies have demonstrated that two drugs, decitabine and gemcitabine, have potent anti-HIV-1 activities and can work together in synergy to reduce HIV-1 infectivity via lethal mutagenesis. For their current indications, decitabine and gemcitabine are delivered intravenously.
As an initial step towards the clinical translation of these drugs for the treatment of HIV-1 infection, we synthesized decitabine and gemcitabine prodrugs in order to increase drug permeability, which has generally been shown to correlate with increased bioavailability in vivo. In the present study we investigated the permeability, stability and anti-HIV-1 activity of decitabine and gemcitabine prodrugs and selected the divalerate esters of each as candidates for further investigation.
Our results provide the first demonstration of divalerate prodrugs of decitabine and gemcitabine that are readily permeable, stable and possess anti-HIV-1 activity.
These observations predict improved oral availability of decitabine and gemcitabine, and warrant further study of their ability to reduce HIV-1 infectivity in vivo.
已有超过25种药物被批准用于治疗HIV-1复制。除一种药物外，其他所有药物均通过口服给药。先前的研究表明，地西他滨和吉西他滨这两种药物具有强大的抗HIV-1活性，并且可以协同作用，通过致死性诱变降低HIV-1的感染性。就其目前的适应症而言，地西他滨和吉西他滨通过静脉给药。
作为将这些药物用于治疗HIV-1感染进行临床转化的第一步，我们合成了地西他滨和吉西他滨的前药，以提高药物通透性，一般来说，药物通透性与体内生物利用度的提高相关。在本研究中，我们研究了地西他滨和吉西他滨前药的通透性、稳定性及抗HIV-1活性，并选择了每种药物的二戊酸酯作为进一步研究的候选药物。
我们的结果首次证明了地西他滨和吉西他滨的二戊酸酯前药具有良好的通透性、稳定性并具备抗HIV-1活性。
这些观察结果预示着地西他滨和吉西他滨的口服可用性将会提高，并且有必要进一步研究它们在体内降低HIV-1感染性的能力。
