Advances in nucleoside monophosphate prodrugs as anti-HCV agents

Abstract

Nucleoside monophosphate prodrugs that are eventually bioconverted to the active nucleoside triphosphate (NTP) offer the potential to deliver increased intracellular NTP levels and/or organ-specific NTP enhancement. There are several classes of monophosphate prodrugs that have been applied to HCV drug discovery, and some of these approaches are currently being evaluated in humans. This review discusses recent advances in monophosphate prodrug approaches to improve oral absorption, stability and pharmacokinetic profile, including their advantages and potential pitfalls.

Kajian Dok Molekul Mengenai Interaksi antara RNA-Bergantung RNA Polimerase Virus Denggi dan Analog Nukleosida

“…Dengan adanya kumpulan fosfat, langkah fosforilasi analog nukleosida dapat dikurangkan (Öberg 2006) dan masalah kerintangan virus yang tidak mengeluarkan enzim kinase untuk memfosforilasi analog nukleosida (Galmarini et al 2001). Walau bagaimanapun, kehadiran kumpulan fosfat mempunyai cabarannya yang tersendiri dan yang paling utama ialah masalah penyerapan ke dalam sistem sistemik jika diberi secara oral (Bobeck et al 2010). Masalah ini dapat diatasi dengan mereka bentuk analog nukleosida sebagai prodrug (Bobeck et al 2010).…”

“…Walau bagaimanapun, kehadiran kumpulan fosfat mempunyai cabarannya yang tersendiri dan yang paling utama ialah masalah penyerapan ke dalam sistem sistemik jika diberi secara oral (Bobeck et al 2010). Masalah ini dapat diatasi dengan mereka bentuk analog nukleosida sebagai prodrug (Bobeck et al 2010).…”

Overcoming Stability Challenges in the Quantification of Tissue Nucleotides: Determination of 2′-<i>C</i>-Methylguanosine Triphosphate Concentration in Mouse Liver

“…[8][9][10][11][12] For this class of compounds, the active entity is nucleoside triphosphate (NTP). The NTPs have poor cellular uptake and they undergo rapid enzymatic degradation.…”

“…7) The development of nucleoside and nucleotide analogue molecules have also been key to the evolution of HCV treatment as inhibitors of the important viral replication step catalyzed by HCV NS5B RNA polymerase. [8][9][10][11][12] For this class of compounds, the active entity is nucleoside triphosphate (NTP). The NTPs have poor cellular uptake and they undergo rapid enzymatic degradation.…”

“…To overcome these difficulties prodrug versions of these molecules have been developed to deliver and target nucleosides to the liver for HCV and address bioavailability and stability issues. [7][8][9]11,13,14) 2′-C-Methylguanosine triphosphate or 2′-MeGTP is a nucleotide analog which effectively disrupts RNA formation by the viral polymerase. 8) IDX184 (Fig.…”