Tomas Cihlar1. 1. Gilead Sciences, Foster City, California 94404, USA. tomas.cihlar@gilead.com
Abstract
PURPOSE OF REVIEW: This review describes the class of nucleotide HIV reverse transcriptase inhibitors and summarises recent findings related to tenofovir and its oral prodrug tenofovir disoproxil fumarate, currently the only nucleotide approved for the treatment of HIV infection. In addition, novel strategies in the design of anti-HIV nucleotides and their prodrugs are discussed. RECENT FINDINGS: A number of studies have demonstrated a potent and durable clinical efficacy of tenofovir disoproxil fumarate in combination with other antiretrovirals, particularly lamivudine or emtricitabine and efavirenz. The prophylactic antiretroviral effect of tenofovir and tenofovir disoproxil fumarate has been characterized in various animal models and is currently being evaluated in controlled clinical studies. In addition, efficacy of tenofovir disoproxil fumarate against hepatitis B virus has been established and is currently being explored in phase III trials. The identification of GS-7340, an alternative prodrug of tenofovir has raised the possibility of using phosphonoamidates as novel prodrugs allowing for an effective intracellular delivery of nucleotides. SUMMARY: The concept of nucleotides as a novel class of antiretroviral therapeutics has been successfully validated through tenofovir disoproxil fumarate, a nucleotide prodrug that exhibits potent and durable clinical efficacy and favourable safety profile both in treatment-naïve and experienced HIV-infected patients. Several novel nucleotide reverse transcriptase inhibitors such as GS-9148, PMDTA, and PMEO have recently emerged from continuing preclinical drug discovery efforts.
PURPOSE OF REVIEW: This review describes the class of nucleotide HIV reverse transcriptase inhibitors and summarises recent findings related to tenofovir and its oral prodrug tenofovir disoproxil fumarate, currently the only nucleotide approved for the treatment of HIV infection. In addition, novel strategies in the design of anti-HIV nucleotides and their prodrugs are discussed. RECENT FINDINGS: A number of studies have demonstrated a potent and durable clinical efficacy of tenofovir disoproxil fumarate in combination with other antiretrovirals, particularly lamivudine or emtricitabine and efavirenz. The prophylactic antiretroviral effect of tenofovir and tenofovir disoproxil fumarate has been characterized in various animal models and is currently being evaluated in controlled clinical studies. In addition, efficacy of tenofovir disoproxil fumarate against hepatitis B virus has been established and is currently being explored in phase III trials. The identification of GS-7340, an alternative prodrug of tenofovir has raised the possibility of using phosphonoamidates as novel prodrugs allowing for an effective intracellular delivery of nucleotides. SUMMARY: The concept of nucleotides as a novel class of antiretroviral therapeutics has been successfully validated through tenofovir disoproxil fumarate, a nucleotide prodrug that exhibits potent and durable clinical efficacy and favourable safety profile both in treatment-naïve and experienced HIV-infectedpatients. Several novel nucleotide reverse transcriptase inhibitors such as GS-9148, PMDTA, and PMEO have recently emerged from continuing preclinical drug discovery efforts.