Abstract
GS-9148 (2'-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC(50)=12 microM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2'-Fd4AP that is similar to wild-type virus. The 2'-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.
MeSH terms
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology*
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DNA, Mitochondrial / drug effects
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Fluorine / chemistry*
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Guanosine / analogs & derivatives*
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Guanosine / chemical synthesis*
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Guanosine / chemistry
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Guanosine / pharmacology*
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HIV Reverse Transcriptase / genetics
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Humans
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Molecular Structure
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Nucleosides / chemical synthesis*
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Nucleosides / chemistry
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Nucleosides / pharmacology*
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Organophosphonates / chemical synthesis*
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Organophosphonates / chemistry
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Organophosphonates / pharmacology*
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Zidovudine / pharmacology
Substances
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Anti-HIV Agents
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DNA, Mitochondrial
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Nucleosides
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Organophosphonates
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Reverse Transcriptase Inhibitors
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Guanosine
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Fluorine
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Zidovudine
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HIV Reverse Transcriptase