TAK-652 Inhibits CCR5-Mediated Human Immunodeficiency Virus Type 1 Infection In Vitro and Has Favorable Pharmacokinetics in Humans

Baba, Masanori; Takashima, Katsunori; Miyake, Hiroshi; Kanzaki, Naoyuki; Teshima, Koichiro; Wang, Xin; Shiraishi, Masayuki; Iizawa, Yuji

doi:10.1128/aac.49.11.4584-4591.2005

Cited by 98 publications

(76 citation statements)

References 28 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the first experiment, the IC 50 of TAK-652 for the wild type was 0.14 nM (Table 2). This value was 3.3-fold higher than that obtained previously (2). When the IC 50 for the escape virus at passage 8 (KK 652-8 ) was compared to that for its control virus (KK C-8 ), no reduction in its susceptibility to TAK-652 was observed in either experiment 1 or 2.…”

Section: Resultscontrasting

confidence: 41%

“…Therefore, we chose the KK strain as the source of R5 HIV-1. In our previous study, TAK-652 was found to inhibit replication of the KK strain with an IC 50 and IC 90 of 0.043 nM and 0.19 nM, respectively (2). Therefore, PBMC cultures were started in the absence or presence of TAK-652 at a concentration of 0.2 nM (almost identical to its IC 90 ).…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, TAK-652 has unique properties with which TAK-220 and other CCR5 antagonists are not endowed. TAK-652 has good oral bioavailability and a long plasma half-life in humans (2). Therefore, it is assumed that TAK-652 is able to retain a plasma concentration sufficiently higher than that required for virus inhibition by once-daily administration at a reasonable dose.…”

Section: Discussionmentioning

confidence: 99%

“…TAK-220 is orally bioavailable and highly inhibitory to HIV-1 replication in vitro. The other compound, TAK-652, is a derivative of TAK-779 with high oral bioavailability and favorable pharmacokinetic profiles in humans (2). This compound is also a highly potent inhibitor of R5 HIV-1 replication in vitro.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Isolation and Characterization of Human Immunodeficiency Virus Type 1 Resistant to the Small-Molecule CCR5 Antagonist TAK-652

Baba

Miyake

Wang

et al. 2007

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultscontrasting

confidence: 41%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Isolation and Characterization of Human Immunodeficiency Virus Type 1 Resistant to the Small-Molecule CCR5 Antagonist TAK-652

Baba

Miyake

Wang

et al. 2007

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…Many CCR5 antagonists, such as TAK-779 (6), TAK-220 (7), vicriviroc (VCV) (8), aplaviroc (9), and maraviroc (MVC) (10), have been developed, yet only MVC is clinically used for the treatment of HIV-1-infected patients. Cenicriviroc (CVC; also known as TAK-652 and TBR-652), which is a derivative of TAK-779 with increased bioavailability and potency, is an antagonist of CCR5 and CCR2 (11) and was shown to control HIV-1 replication in vivo when it was used as monotherapy for 10 days (12,13) and in a phase IIb clinical study by Tobira Therapeutics (14).…”

mentioning

confidence: 99%

Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies

Kuwata

Enomoto

Baba

et al. 2016

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

bCenicriviroc is a CCR5 antagonist which prevents human immunodeficiency virus type 1 (HIV-1) from cellular entry. The CCR5-binding regions of the HIV-1 envelope glycoprotein are important targets for neutralizing antibodies (NAbs), and mutations conferring cenicriviroc resistance may therefore affect sensitivity to NAbs. Here, we used the in vitro induction of HIV-1 variants resistant to cenicriviroc or NAbs to examine the relationship between resistance to cenicriviroc and resistance to NAbs. The cenicriviroc-resistant variant KK 652-67 (strain KK passaged 67 times in the presence of increasing concentrations of cenicriviroc) was sensitive to neutralization by NAbs against the V3 loop, the CD4-induced (CD4i) region, and the CD4-binding site (CD4bs), whereas the wild-type (WT) parental HIV-1 strain KK WT from which cenicriviroc-resistant strain KK 652-67 was obtained was resistant to these NAbs. The V3 region of KK 652-67 was important for cenicriviroc resistance and critical to the high sensitivity of the V3, CD4i, and CD4bs epitopes to NAbs. Moreover, induction of variants resistant to anti-V3 NAb 0.5␥ and anti-CD4i NAb 4E9C from cenicriviroc-resistant strain KK 652-67 resulted in reversion to the cenicriviroc-sensitive phenotype comparable to that of the parental strain, KK WT . Resistance to 0.5␥ and 4E9C was caused by the novel substitutions R315K, G324R, and E381K in the V3 and C3 regions near the substitutions conferring cenicriviroc resistance. Importantly, these amino acid changes in the CCR5-binding region were also responsible for reversion to the cenicriviroc-sensitive phenotype. These results suggest the presence of key amino acid residues where resistance to cenicriviroc is incompatible with resistance to NAbs. This implies that cenicriviroc and neutralizing antibodies may restrict the emergence of variants resistant to each other.

show abstract

CCR 5 Antagonists: Small‐Molecule Inhibitors For Blocking HIV ‐1 Entry

Tagat¹

2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

TAK-652 Inhibits CCR5-Mediated Human Immunodeficiency Virus Type 1 Infection In Vitro and Has Favorable Pharmacokinetics in Humans

Cited by 98 publications

References 28 publications

Isolation and Characterization of Human Immunodeficiency Virus Type 1 Resistant to the Small-Molecule CCR5 Antagonist TAK-652

Isolation and Characterization of Human Immunodeficiency Virus Type 1 Resistant to the Small-Molecule CCR5 Antagonist TAK-652

Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies

CCR 5 Antagonists: Small‐Molecule Inhibitors For Blocking HIV ‐1 Entry

Contact Info

Product

Resources

About