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Antimicrobial Agents and Chemotherapy, February 2002, p. 402-408, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.402-408.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Oxidative Modifications of Kynostatin-272, a Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor: Potential Mechanism for Altered Activity in Monocytes/Macrophages

David A. Davis,^1* Elizabeth Read-Connole,¹ Kara Pearson,² Henry M. Fales,² Fonda M. Newcomb,¹ Jackob Moskovitz,² and Robert Yarchoan¹

HIV and AIDS Malignancy Branch, National Cancer Institute,¹ Laboratory of Biophysical Chemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892²

Received 22 May 2001/ Returned for modification 10 September 2001/ Accepted 23 October 2001

Previous studies have indicated that human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) are less active at blocking viral replication in HIV-1 infected peripheral blood monocytes/macrophages (M/M) than in HIV-1-infected T cells. We explored the hypothesis that oxidative modification and/or metabolism of the PIs in M/M might account for this reduced potency. We first tested the susceptibility of several PIs (kynostatin-272 [KNI-272], saquinavir, indinavir, ritonavir, or JE-2147) to oxidation after exposure to hydrogen peroxide (H₂O₂): only KNI-272 was highly susceptible to oxidation. Treatment of KNI-272 with low millimolar concentrations of H₂O₂ resulted in mono-oxidation of the sulfur in the S-methyl cysteine (methioalanine) moiety, as determined by reversed-phase high-performance liquid chromatography and mass spectrometry (RP-HPLC/MS). Higher concentrations of H₂O₂ led to an additional oxidation of the sulfur in the thioproline moiety of KNI-272. None of the PIs were metabolized or oxidized when added to T cells and cultured for up to 12 days. However, when KNI-272 was added to M/M, the concentration of the original KNI-272 steadily decreased with a corresponding increase in the production of three KNI-272 metabolites as identified by RP-HPLC/MS. The structures of these metabolites were different from those produced by H₂O₂ treatment. The two major products of M/M metabolism of KNI-272 were identified as isomeric forms of KNI-272 oxidized solely on the thioproline ring. Both metabolites had reduced capacities to inhibit HIV-1 protease activity when tested in a standard HIV-1 protease assay. These studies demonstrate that antiviral compounds can be susceptible to oxidative modification in M/M and that this can affect their antiviral potency.

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* Corresponding author. Mailing address: HIV and AIDS Malignancy Branch, National Cancer Institute, NIH, Bldg. 10, Rm. 10S255, 9000 Rockville Pike, Bethesda, MD 20892-1868. Phone: (301) 402-3630. Fax: (301) 402-3645. E-mail: dadavis{at}helix.nih.gov.

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Antimicrobial Agents and Chemotherapy, February 2002, p. 402-408, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.402-408.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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