GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-
furan-2-yloxymethyl)
phosphonic acid] is a novel
ribose-modified human immunodeficiency virus type 1 (HIV-1)
nucleotide reverse transcriptase (RT) inhibitor (NRTI) selected from a series of
nucleoside phosphonate analogs for its favorable in vitro
biological properties including (i) a low potential for mitochondrial toxicity, (ii) a minimal cytotoxicity in renal proximal tubule cells and other cell types, (iii) synergy in combination with other antiretrovirals, and (iv) a unique resistance profile against multiple NRTI-resistant HIV-1 strains. Notably,
antiviral resistance analysis indicated that neither the K65R, L74V, or M184V RT mutation nor their combinations had any effect on the antiretroviral activity of
GS-9148. Viruses carrying four or more
thymidine analog mutations showed a substantially smaller change in
GS-9148 activity relative to that observed with most marketed NRTIs.
GS-9131, an ethylalaninyl phosphonoamidate
prodrug designed to maximize the intracellular delivery of
GS-9148, is a potent inhibitor of multiple subtypes of HIV-1 clinical isolates, with a mean 50% effective concentration of 37 nM. Inside cells,
GS-9131 is readily hydrolyzed to
GS-9148, which is further phosphorylated to its active
diphosphate metabolite (A. S. Ray, J. E. Vela, C. G. Boojamra, L. Zhang, H. Hui, C. Callebaut, K. Stray, K.-Y. Lin, Y. Gao, R. L. Mackman, and T. Cihlar, Antimicrob. Agents Chemother. 52:648-654, 2008).
GS-9148 diphosphate acts as a competitive inhibitor of RT with respect to dATP (K(i) = 0.8 muM) and exhibits low inhibitory potency against host polymerases including
DNA polymerase gamma.
Oral administration of
GS-9131 to beagle dogs at a dose of 3 mg/kg of
body weight resulted in high and persistent levels of
GS-9148 diphosphate in peripheral blood mononuclear cells (with a maximum intracellular concentration of >9 microM and a half-life of >24 h). This favorable preclinical profile makes
GS-9131 an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV.