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Antimicrobial Agents and Chemotherapy, October 2002, p. 3292-3297, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3292-3297.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inhibition of Human Immunodeficiency Virus Type 1 Integration by Diketo Derivatives

Wim Pluymers,1 Godwin Pais,2 Bénédicte Van Maele,1 Christophe Pannecouque,1 Valery Fikkert,1 Terrence R. Burke Jr.,2 Erik De Clercq,1 Myriam Witvrouw,1 Nouri Neamati,3 and Zeger Debyser1*

Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium,1 Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702,2 School of Pharmacy, University of Southern California, Los Angeles, California 900893

Received 17 January 2002/ Returned for modification 23 April 2002/ Accepted 15 July 2002

A series of diketo derivatives was found to inhibit human immunodeficiency virus type 1 (HIV-1) integrase activity. Only L-708,906 inhibited the replication of HIV-1(IIIB) (50% effective concentration, 12 µM), HIV-1 clinical strains, HIV-1 strains resistant to reverse transcriptase or fusion inhibitors, HIV-2 (ROD strain) and simian immunodeficiency virus (MAC251). The combinations of L-708,906 with zidovudine, nevirapine, or nelfinavir proved to be subsynergistic. In cell culture, addition of L-708,906 could be postponed for 7 h after infection, a moment coinciding with HIV integration. Inhibition of integration in cell culture was confirmed by quantitative Alu-PCR.

* Corresponding author. Mailing address: Rega Institute for Medical Research, K.U. Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium. Phone: 32 16 33 21 83. Fax: 32 16 33 21 31. E-mail: zeger.debyser{at}uz.kuleuven.ac.be.

Antimicrobial Agents and Chemotherapy, October 2002, p. 3292-3297, Vol. 46, No. 10
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.10.3292-3297.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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