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

Constantine G. Boojamra; Richard L. Mackman; David Y. Markevitch; Vidya Prasad; Adrian S. Ray; Janet Douglas; Deborah Grant; Choung U. Kim; Tomas Cihlar

doi:10.1016/j.bmcl.2007.11.125

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

Constantine G. Boojamra, Richard L. Mackman, David Y. Markevitch, Vidya Prasad, Adrian S. Ray, Janet Douglas, Deborah Grant, Choung U. Kim, Tomas Cihlar

Vaccine and Gene Therapy Institute

Research output: Contribution to journal › Article

50 Scopus citations

Abstract

GS-9148 (2′-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC₅₀ = 12 μM). 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.

Original language	English (US)
Pages (from-to)	1120-1123
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2007.11.125
State	Published - Feb 1 2008

Keywords

Antiviral
HIV
Phosphonate
Resistance

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Boojamra, C. G., Mackman, R. L., Markevitch, D. Y., Prasad, V., Ray, A. S., Douglas, J., Grant, D., Kim, C. U., & Cihlar, T. (2008). Synthesis and anti-HIV activity of GS-9148 (2′-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor. Bioorganic and Medicinal Chemistry Letters, 18(3), 1120-1123. https://doi.org/10.1016/j.bmcl.2007.11.125

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; Grant, Deborah; Kim, Choung U.; Cihlar, Tomas.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 18, No. 3, 01.02.2008, p. 1120-1123.

Research output: Contribution to journal › Article

Boojamra, Constantine G. ; Mackman, Richard L. ; Markevitch, David Y. ; Prasad, Vidya ; Ray, Adrian S. ; Douglas, Janet ; Grant, Deborah ; Kim, Choung U. ; Cihlar, Tomas. / Synthesis and anti-HIV activity of GS-9148 (2′-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor. In: Bioorganic and Medicinal Chemistry Letters. 2008 ; Vol. 18, No. 3. pp. 1120-1123.

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