Synthesis and anti-HIV activity of GS-9148 (2′-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor

Boojamra, Constantine G.; Mackman, Richard L.; Markevitch, David Y.; Prasad, Vidya; Ray, Adrian S.; Douglas, Janet L.; Grant, David; Kim, Choung U.; Cihlář, Tomáš

doi:10.1016/j.bmcl.2007.11.125

Cited by 57 publications

(19 citation statements)

References 28 publications

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“…GS-9148-DP was synthesized by the Medicinal Chemistry Department of Gilead Sciences. 5 To obtain ternary complexes with GS-9148-DP and dATP, RT(P•ddCMP) crystals were placed into the dehydration solution with 1 mM GS-9148-DP or dATP. Crystals of RT(P•GS-9148) complex were grown under the same conditions as RT(P•ddCMP) and subjected to the dehydration solution for 1 day.…”

Section: Crystallization and Data Collectionmentioning

confidence: 99%

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Visualizing the Molecular Interactions of a Nucleotide Analog, GS-9148, with HIV-1 Reverse Transcriptase–DNA Complex

Lansdon

Samuel

Lagpacan

et al. 2010

Journal of Molecular Biology

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Section: Crystallization and Data Collectionmentioning

confidence: 99%

“…1). 5 Fluorine was added at the 2′-position to enhance the selectivity of the active metabolite GS-9148-diphosphate (DP) for RT over the mitochondrial DNA polymerase γ. 6 Unlike other nucleotide analogs, GS-9148 has also shown a low potential for renal toxicity in preclinical studies.…”

Section: Introductionmentioning

confidence: 99%

Visualizing the Molecular Interactions of a Nucleotide Analog, GS-9148, with HIV-1 Reverse Transcriptase–DNA Complex

Lansdon

Samuel

Lagpacan

et al. 2010

Journal of Molecular Biology

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“…GS-9148 was synthesized as previously described (2). Tenofovir, adefovir, and cidofovir were provided by the Process Chemistry Department, Gilead Sciences.…”

Section: Methodsmentioning

confidence: 99%

Novel Nucleotide Human Immunodeficiency Virus Reverse Transcriptase Inhibitor GS-9148 with a Low Nephrotoxic Potential: Characterization of Renal Transport and Accumulation

Cihlář

Laflamme

Fisher³

et al. 2009

Antimicrob Agents Chemother

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Accumulation of antiviral nucleotides in renal proximal tubules is controlled by their basolateral uptake via the human renal organic anion transporters type 1 (hOAT1) and 3 (hOAT3) and apical efflux via the multidrug resistance protein 4 (MRP4). GS-9148 is a novel ribose-modified nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitor, and its oral prodrug GS-9131 is currently being evaluated in the clinic as an anti-HIV agent. To assess the potential of GS-9148 for nephrotoxicity, its mechanism of renal transport, cytotoxicity, and renal accumulation were explored in vitro and in vivo. In comparison with the acyclic nucleotides cidofovir, adefovir, and tenofovir, GS-9148 showed 60-to 100-fold lower efficiency of transport (V max /K m ) by hOAT1 and was 20-to 300-fold less cytotoxic in cells overexpressing hOAT1, indicating its lower hOAT1-mediated intracellular accumulation and reduced intrinsic cytotoxicity. GS-9148 was also relatively inefficiently transported by hOAT3. Similar to acyclic nucleotides, GS-9148 was a substrate for MRP4 as evidenced by its reduced intracellular retention in cells overexpressing the efflux pump. Consistent with these molecular observations, GS-9148 was inefficiently taken up by fresh human renal cortex tissue in vitro and showed a limited accumulation in kidneys in vivo following oral administration of [ 14 C]GS-9131 to dogs. Compared to acyclic nucleotide analogs, GS-9148 was also found to have lower net active tubular secretion in dogs. Collectively, these results suggest that GS-9148 exhibits a low potential for renal accumulation and nephrotoxicity.

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“…GS-9148 undergoes two phosphorylations to become GS-9148-diphosphate (GS-9148-DP), which, like tenofovir-DP, is the active metabolite that is incorporated by HIV-1 RT. In contrast to tenofovir, GS-9148 is composed of a 2Ј,3Ј-dihydrofuran that contains a 2Ј-fluoro group (2) (Fig. 1).…”

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Mechanism of Resistance to GS-9148 Conferred by the Q151L Mutation in HIV-1 Reverse Transcriptase

Scarth

White

Chen

et al. 2011

Antimicrob Agents Chemother

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GS-9148 is an investigational phosphonate nucleotide analogue inhibitor of reverse transcriptase (RT) (NtRTI) of human immunodeficiency virus type 1 (HIV-1). This compound is an adenosine derivative with a 2,3-dihydrofuran ring structure that contains a 2-fluoro group. The resistance profile of GS-9148 is unique in that the inhibitor can select for the very rare Q151L mutation in HIV-1 RT as a pathway to resistance. Q151L is not stably selected by any of the approved nucleoside or nucleotide analogues; however, it may be a transient intermediate that leads to the related Q151M mutation, which confers resistance to multiple compounds that belong to this class of RT inhibitors. Here, we employed pre-steady-state kinetics to study the impact of Q151L on substrate and inhibitor binding and the catalytic rate of incorporation. Most importantly, we found that the Q151L mutant is unable to incorporate GS-9148 under single-turnover conditions. Interference experiments showed that the presence of GS-9148-diphosphate, i.e., the active form of the inhibitor, does not reduce the efficiency of incorporation for the natural counterpart. We therefore conclude that Q151L severely compromises binding of GS-9148-diphosphate to RT. This effect is highly specific, since we also demonstrate that another NtRTI, tenofovir, is incorporated with selectivity similar to that seen with wild-type RT. Incorporation assays with other related compounds and models based on the RT/DNA/GS-9148-diphosphate crystal structure suggest that the 2-fluoro group of GS-9148 may cause steric hindrance with the side chain of the Q151L mutant.The DNA polymerase activity of HIV-1 reverse transcriptase (RT) is targeted by nucleos(t)ide analogue RT inhibitors [N(t)RTIs], which represent the backbone of frequently used drug regimens. N(t)RTIs compete with natural deoxynucleoside triphosphate (dNTP) pools for incorporation and cause chain termination. There are currently seven approved NRTIs available for the treatment of HIV-1 infection (7). The only approved NtRTI, i.e., tenofovir, is a phosphonate with an acyclic linker attached to the adenine base (7). An investigational NtRTI, GS-9148, has recently been shown to be active against HIV-1 in cell culture and to possess a promising resistance profile in addition to a low nephrotoxic potential (4, 5). GS-9148 is the intracellularly metabolized form of the orally bioavailable phosphonate GS-9131 (29) (Fig. 1). GS-9148 undergoes two phosphorylations to become GS-9148-diphosphate (GS-9148-DP), which, like tenofovir-DP, is the active metabolite that is incorporated by HIV-1 RT. In contrast to tenofovir, GS-9148 is composed of a 2Ј,3Ј-dihydrofuran that contains a 2Ј-fluoro group (2) (Fig. 1).In vitro selection experiments in cell culture revealed the emergence of two different resistance pathways. The compound selects either for Q151L, with high-level resistance to GS-9148 (16), or for a combination of K70E, D123N, and T165I, which shows low-level resistance to . Q151L is a potential intermediate in the development of...

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Synthesis and anti-HIV activity of GS-9148 (2′-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor

Cited by 57 publications

References 28 publications

Visualizing the Molecular Interactions of a Nucleotide Analog, GS-9148, with HIV-1 Reverse Transcriptase–DNA Complex

Visualizing the Molecular Interactions of a Nucleotide Analog, GS-9148, with HIV-1 Reverse Transcriptase–DNA Complex

Novel Nucleotide Human Immunodeficiency Virus Reverse Transcriptase Inhibitor GS-9148 with a Low Nephrotoxic Potential: Characterization of Renal Transport and Accumulation

Mechanism of Resistance to GS-9148 Conferred by the Q151L Mutation in HIV-1 Reverse Transcriptase

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