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Antimicrobial Agents and Chemotherapy, April 2001, p. 1225-1230, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1225-1230.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Anti-Human Immunodeficiency Virus Activity of YK-FH312 (a Betulinic Acid Derivative), a Novel Compound Blocking Viral Maturation

Taisei Kanamoto,1 Yoshiki Kashiwada,2 Kenji Kanbara,1 Kazuyo Gotoh,1 Manabu Yoshimori,1 Toshiyuki Goto,3 Kouichi Sano,3 and Hideki Nakashima1,*

Department of Microbiology and Immunology, Kagoshima University Dental School, 8-35-1 Sakuragaoka, Kagoshima 890-8544,1 Niigata College of Pharmacy, Niigata 950-2081,2 and Department of Microbiology, Osaka Medical College, 2-7 Daigaku-machi, Osaka 569-8686,3 Japan

Received 21 August 2000/Returned for modification 15 November 2000/Accepted 24 January 2001

Betulinic acid, a triterpenoid isolated from the methyl alcohol extract of the leaves of Syzigium claviflorum, was found to have a potent inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Betulinic acid derivatives were synthesized to enhance the anti-HIV activity. Among the derivatives, 3-O-(3',3'-dimethylsuccinyl) betulinic acid, designated YK-FH312, showed the highest activity against HIV-induced cytopathic effects in HIV-1-infected MT-4 cells. To determine the step(s) of HIV replication affected by YK-FH312, a syncytium formation inhibition assay in MOLT-4/HIV-1IIIB and MOLT-4 coculture, a multinuclear-activation-of-galactosidase-indicator (MAGI) assay in MAGI-CCR5 cells, electron microscopic observation, and a time-of-addition assay were performed. In the syncytium formation inhibition assay or in the MAGI assay for de novo infection, the compound did not show inhibitory effects against HIV replication. Conversely, no virions were detected in HIV-1-infected cell cultures treated with YK-FH312 either by electron microscopic observation or by viral yield in the supernatant. In accordance with a p24 enzyme-linked immunosorbent assay of culture supernatant in the time-of-addition assay, YK-FH312 inhibited virus expression in the supernatant when it was added 18 h postinfection. However, Western blot analysis of the cells in the time-of-addition assay revealed that the production of viral proteins in the cells was not inhibited completely by YK-FH312. These results suggest that YK-FH312 might affect the step(s) of virion assembly and/or budding of virions, and this is a novel mechanism of action of an anti-HIV compound.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Kagoshima University Dental School, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan. Phone: 81-99-275-6150. Fax: 81-99-275-6158. E-mail: hidekin{at}dentb.hal.kagoshima-u.ac.jp.

Antimicrobial Agents and Chemotherapy, April 2001, p. 1225-1230, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1225-1230.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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