In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile.
GS-8374 is a novel bis-tetrahydrofuran HIV-1 protease (PR) inhibitor (PI) with a unique diethylphosphonate moiety. It was selected from a series of analogs containing various di(alkyl)phosphonate substitutions connected via a linker to the para position of a P-1 phenyl ring. GS-8374 inhibits HIV-1 PR with high potency (K(i) = 8.1 pM) and with no known effect on host proteases. Kinetic and thermodynamic analysis of GS-8374 binding to PR demonstrated an extremely slow off rate for the inhibitor and favorable contributions of both the enthalpic and entropic components to the total free binding energy. GS-8374 showed potent antiretroviral activity in T-cell lines, primary CD4(+) T cells (50% effective concentration [EC(50)] = 3.4 to 11.5 nM), and macrophages (EC(50) = 25.5 nM) and exhibited low cytotoxicity in multiple human cell types. The antiviral potency of GS-8374 was only moderately affected by human serum protein binding, and its combination with multiple approved antiretrovirals showed synergistic effects. When it was tested in a PhenoSense assay against a panel of 24 patient-derived viruses with high-level PI resistance, GS-8374 showed lower mean EC(50)s and lower fold resistance than any of the clinically approved PIs. Similar to other PIs, in vitro hepatic microsomal metabolism of GS-8374 was efficiently blocked by ritonavir, suggesting a potential for effective pharmacokinetic boosting in vivo. In summary, results from this broad in vitro pharmacological profiling indicate that GS-8374 is a promising candidate to be further assessed as a new antiretroviral agent with potential for clinical efficacy in both treatment-naïve and -experienced patients.
Gilead Sciences, 333 Lakeside Dr., Foster City, CA 94404, USA. christian.callebaut@gilead.com
Christian
C
Callebaut
Kirsten
K
Stray
Luong
L
Tsai
Matt
M
Williams
Zheng-Yu
ZY
Yang
Carina
C
Cannizzaro
Stephanie A
SA
Leavitt
Xiaohong
X
Liu
Kelly
K
Wang
Bernard P
BP
Murray
Andrew
A
Mulato
Marcos
M
Hatada
Tina
T
Priskich
Neil
N
Parkin
Swami
S
Swaminathan
William
W
Lee
Gong-Xin
GX
He
Lianhong
L
Xu
Tomas
T
Cihlar
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002151:Calorimetry; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
D017320:HIV Protease Inhibitors; D063065:Organophosphonates; D016333:HIV Protease; D046988:Proteasome Endopeptidase Complex
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