| Reference | 1. Antimicrob Agents Chemother. 2007 Feb;51(2):707-15. Epub 2006 Nov 20. <br />
Isolation and characterization of human immunodeficiency virus type 1 resistant
to the small-molecule CCR5 antagonist TAK-652. <br />
Baba M(1), Miyake H, Wang X, Okamoto M, Takashima K. <br />
Author information: <br />
(1)Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases,
Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1,
Sakuragaoka, Kagoshima 890-8544, Japan. [email protected] <br />
TAK-652, a novel small-molecule chemokine receptor antagonist, is a highly potent
and selective inhibitor of CCR5-using (R5) human immunodeficiency virus type 1
(HIV-1) replication in vitro. Since TAK-652 is orally bioavailable and has
favorable pharmacokinetic profiles in humans, it is considered a promising
candidate for an entry inhibitor of HIV-1. To investigate the resistance to
TAK-652, peripheral blood mononuclear cells were infected with the R5 HIV-1
primary isolate KK and passaged in the presence of escalating concentrations of
the compound for more than 1 year. After 67 weeks of cultivation, the escape
virus emerged even in the presence of a high concentration of TAK-652. This virus
displayed more than 200,000-fold resistance to TAK-652 compared with the wild
type. The escape virus appeared to have cross-resistance to the structurally
related compound TAK-779 but retained full susceptibility to TAK-220, which is
from a different class of CCR5 antagonists. Furthermore, the escape virus was
unable to use CXCR4 as a coreceptor. Analysis for Env amino acid sequences of
escape viruses at certain points of passage revealed that amino acid changes
accumulated with an increasing number of passages. Several amino acid changes not
only in the V3 region but also in other Env regions seemed to be required for R5
HIV-1 to acquire complete resistance to TAK-652. <br />
2. Antimicrob Agents Chemother. 2005 Nov;49(11):4584-91. <br />
TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in
vitro and has favorable pharmacokinetics in humans. <br />
Baba M(1), Takashima K, Miyake H, Kanzaki N, Teshima K, Wang X, Shiraishi M,
Iizawa Y. <br />
Author information: <br />
(1)Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases,
Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1,
Sakuragaoka, Kagoshima 890-8544, Japan. [email protected] <br />
The first small-molecule CCR5 antagonist, TAK-779, could not be developed as an
anti-human immunodeficiency virus type (anti-HIV-1) agent because of its poor
oral bioavailability. TAK-652 is an orally bioavailable TAK-779 derivative with
potent anti-HIV-1 activity. TAK-652 inhibited the binding of RANTES (regulated on
activation, normal T-cell expressed and secreted), macrophage inflammatory
protein 1alpha (MIP-1alpha), and MIP-1beta to CCR5-expressing cells at nanomolar
concentrations. TAK-652 could also suppress the binding of monocyte chemotactic
protein 1 (MCP-1) to CCR2b-expressing cells. However, its inhibitory effect on
ligand binding to other chemokine receptors was limited. TAK-652 was active
against CCR5-using (R5) HIV-1 but totally inactive against CXCR4-using (X4)
HIV-1. The compound was active against R5 HIV-1 clinical isolates containing
reverse transcriptase and protease inhibitor-resistant mutations, with a mean 50%
effective concentration (EC50) and EC90 of 0.061 and 0.25 nM, respectively. In
addition, recombinant R5 viruses carrying different subtype (A to G) envelope
proteins were equally susceptible to TAK-652. A single oral administration of
TAK-652 up to 100 mg was safe and well tolerated in humans. The compound
displayed favorable pharmacokinetics, and its plasma concentration was 7.2 ng/ml
(9.1 nM) even 24 h after the administration of 25 mg. Thus, TAK-652 is a
promising candidate as a novel entry inhibitor of HIV-1.
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