DOI: 10.1128/jvi.78.16.8654-8662.2004. Spirodiketopiperazine-Based CCR5 Inhibitor Which Preserves CC-Chemokine/CCR5 Interactions and Exerts Potent Activity against R5 Human Immunodeficiency Virus Type 1 In Vitro

Spirodiketopiperazine-Based CCR5 Inhibitor Which Preserves CC-Chemokine/CCR5 Interactions and Exerts Potent Activity against R5 Human Immunodeficiency Virus Type 1 In Vitro

10.1128/jvi.78.16.8654-8662.2004

Crossref journal-article

American Society for Microbiology

Journal of Virology (235)

Abstract

ABSTRACT We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ONO4128/GW873140, which specifically blocked the binding of macrophage inflammatory protein 1α (MIP-1α) to CCR5 with a high affinity ( K d of ≈3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCR5 binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (HIV-1 MDR ) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCR5. AK602, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1β binding to CCR5 + cells and their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCR5 interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection.

Bibliography

Maeda, K., Nakata, H., Koh, Y., Miyakawa, T., Ogata, H., Takaoka, Y., Shibayama, S., Sagawa, K., Fukushima, D., Moravek, J., Koyanagi, Y., & Mitsuya, H. (2004). Spirodiketopiperazine-Based CCR5 Inhibitor Which Preserves CC-Chemokine/CCR5 Interactions and Exerts Potent Activity against R5 Human Immunodeficiency Virus Type 1 In Vitro. Journal of Virology, 78(16), 8654â8662.

Authors 12

Kenji Maeda (first)
Hirotomo Nakata (additional)
Yasuhiro Koh (additional)
Toshikazu Miyakawa (additional)
Hiromi Ogata (additional)
Yoshikazu Takaoka (additional)
Shiro Shibayama (additional)
Kenji Sagawa (additional)
Daikichi Fukushima (additional)
Joseph Moravek (additional)
Yoshio Koyanagi (additional)
Hiroaki Mitsuya (additional)

References 36 Referenced 195

10.1073/pnas.96.10.5698
10.1126/science.273.5283.1856
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Evans E. A. 1974. Catalytic exchange in solution p. 271-317. In Tritium and its compounds. Wiley and Sons New York N.Y.
10.1038/nm0703-839
10.1038/8394
10.1016/S0140-6736(00)04898-4
10.1126/science.3014648
10.1016/S1521-6616(03)00059-7
Gribble, G. W. 1975. Reactions of sodium borohydride in acidic media. Selective reduction of aldehydes with sodium triacetoborohydride. JCS Chem. Comm.1975:535-541. / JCS Chem. Comm. (1975)
Kavlick, M. F., and H. Mitsuya. 2001. The emergence of drug-resistant human immunodeficiency virus type 1 variants and its impact on antiretroviral therapy of human immunodeficiency virus type 1 infection, p. 279-312. In E. de Clerq (ed.), The art of antiretroviral therapy. American Society for Microbiology, Washington, D.C. / The art of antiretroviral therapy (2001)
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Dates

Type	When
Created	21 years, 1 month ago (July 27, 2004, 2:42 p.m.)
Deposited	3 years, 6 months ago (March 5, 2022, 3:37 a.m.)
Indexed	1 week ago (Aug. 30, 2025, 12:53 p.m.)
Issued	21 years ago (Aug. 15, 2004)
Published	21 years ago (Aug. 15, 2004)
Published Print	21 years ago (Aug. 15, 2004)

Funders 0

None

BibTeX

@article{Maeda_2004, title={Spirodiketopiperazine-Based CCR5 Inhibitor Which Preserves CC-Chemokine/CCR5 Interactions and Exerts Potent Activity against R5 Human Immunodeficiency Virus Type 1 In Vitro}, volume={78}, ISSN={1098-5514}, url={http://dx.doi.org/10.1128/jvi.78.16.8654-8662.2004}, DOI={10.1128/jvi.78.16.8654-8662.2004}, number={16}, journal={Journal of Virology}, publisher={American Society for Microbiology}, author={Maeda, Kenji and Nakata, Hirotomo and Koh, Yasuhiro and Miyakawa, Toshikazu and Ogata, Hiromi and Takaoka, Yoshikazu and Shibayama, Shiro and Sagawa, Kenji and Fukushima, Daikichi and Moravek, Joseph and Koyanagi, Yoshio and Mitsuya, Hiroaki}, year={2004}, month=aug, pages={8654–8662} }

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