Abstract
A series of triterpene compounds characterized by a stringent structure-activity relationship were identified as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. Currently studied botulinic derivatives have 50% inhibitory concentrations (IC50) against HIV-1 strain IIIB/LAI in the 10 nM range in several cellular infection assays but are inactive against HIV-2. These compounds did not significantly inhibit the in vitro activities of several purified HIV-1 enzymes. Rather, they appeared to block virus infection at a postbinding, envelope-dependent step involved in the fusion of the virus to the cell membrane.
Full text
PDF![3564](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca90/43620/c6d3a71cfb79/pnas01131-0096.png)
![3565](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca90/43620/ae84caebd9bf/pnas01131-0097.png)
![3566](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca90/43620/369c902ecdbc/pnas01131-0098.png)
![3567](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca90/43620/f95065f517ce/pnas01131-0099.png)
![3568](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca90/43620/4d9c566ecc3b/pnas01131-0100.png)
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bergeron L., Sullivan N., Sodroski J. Target cell-specific determinants of membrane fusion within the human immunodeficiency virus type 1 gp120 third variable region and gp41 amino terminus. J Virol. 1992 Apr;66(4):2389–2397. doi: 10.1128/jvi.66.4.2389-2397.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Carteau S., Mouscadet J. F., Goulaouic H., Subra F., Auclair C. Quantitative in vitro assay for human immunodeficiency virus deoxyribonucleic acid integration. Arch Biochem Biophys. 1993 Feb 1;300(2):756–760. doi: 10.1006/abbi.1993.1105. [DOI] [PubMed] [Google Scholar]
- Charneau P., Alizon M., Clavel F. A second origin of DNA plus-strand synthesis is required for optimal human immunodeficiency virus replication. J Virol. 1992 May;66(5):2814–2820. doi: 10.1128/jvi.66.5.2814-2820.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ciminale V., Felber B. K., Campbell M., Pavlakis G. N. A bioassay for HIV-1 based on Env-CD4 interaction. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1281–1287. doi: 10.1089/aid.1990.6.1281. [DOI] [PubMed] [Google Scholar]
- Connolly K. J., Hammer S. M. Antiretroviral therapy: strategies beyond single-agent reverse transcriptase inhibition. Antimicrob Agents Chemother. 1992 Mar;36(3):509–520. doi: 10.1128/aac.36.3.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Craigie R., Mizuuchi K., Bushman F. D., Engelman A. A rapid in vitro assay for HIV DNA integration. Nucleic Acids Res. 1991 May 25;19(10):2729–2734. doi: 10.1093/nar/19.10.2729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Daar E. S., Li X. L., Moudgil T., Ho D. D. High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6574–6578. doi: 10.1073/pnas.87.17.6574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- De Clercq E. Basic approaches to anti-retroviral treatment. J Acquir Immune Defic Syndr. 1991;4(3):207–218. [PubMed] [Google Scholar]
- De Clercq E., Yamamoto N., Pauwels R., Baba M., Schols D., Nakashima H., Balzarini J., Debyser Z., Murrer B. A., Schwartz D. Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5286–5290. doi: 10.1073/pnas.89.12.5286. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Debyser Z., Pauwels R., Andries K., Desmyter J., Kukla M., Janssen P. A., De Clercq E. An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1451–1455. doi: 10.1073/pnas.88.4.1451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dragic T., Charneau P., Clavel F., Alizon M. Complementation of murine cells for human immunodeficiency virus envelope/CD4-mediated fusion in human/murine heterokaryons. J Virol. 1992 Aug;66(8):4794–4802. doi: 10.1128/jvi.66.8.4794-4802.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Freed E. O., Myers D. J., Risser R. Identification of the principal neutralizing determinant of human immunodeficiency virus type 1 as a fusion domain. J Virol. 1991 Jan;65(1):190–194. doi: 10.1128/jvi.65.1.190-194.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Helenius A. Unpacking the incoming influenza virus. Cell. 1992 May 15;69(4):577–578. doi: 10.1016/0092-8674(92)90219-3. [DOI] [PubMed] [Google Scholar]
- Hodges T. L., Kahn J. O., Kaplan L. D., Groopman J. E., Volberding P. A., Amman A. J., Arri C. J., Bouvier L. M., Mordenti J., Izu A. E. Phase 1 study of recombinant human CD4-immunoglobulin G therapy of patients with AIDS and AIDS-related complex. Antimicrob Agents Chemother. 1991 Dec;35(12):2580–2586. doi: 10.1128/aac.35.12.2580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnston M. I., Hoth D. F. Present status and future prospects for HIV therapies. Science. 1993 May 28;260(5112):1286–1293. doi: 10.1126/science.7684163. [DOI] [PubMed] [Google Scholar]
- Kieny M. P., Lathe R., Rivière Y., Dott K., Schmitt D., Girard M., Montagnier L., Lecocq J. Improved antigenicity of the HIV env protein by cleavage site removal. Protein Eng. 1988 Sep;2(3):219–225. doi: 10.1093/protein/2.3.219. [DOI] [PubMed] [Google Scholar]
- Lange J. M., Cooper D. A., Danner S. A. Antiretroviral treatment: state of the art and future directions. AIDS. 1991;5 (Suppl 2):S181–S188. [PubMed] [Google Scholar]
- Lemaître M., Henin Y., Destouesse F., Ferrieux C., Montagnier L., Blanchard A. Role of mycoplasma infection in the cytopathic effect induced by human immunodeficiency virus type 1 in infected cell lines. Infect Immun. 1992 Mar;60(3):742–748. doi: 10.1128/iai.60.3.742-748.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Malmqvist M. Biospecific interaction analysis using biosensor technology. Nature. 1993 Jan 14;361(6408):186–187. doi: 10.1038/361186a0. [DOI] [PubMed] [Google Scholar]
- Pauwels R., Balzarini J., Baba M., Snoeck R., Schols D., Herdewijn P., Desmyter J., De Clercq E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods. 1988 Aug;20(4):309–321. doi: 10.1016/0166-0934(88)90134-6. [DOI] [PubMed] [Google Scholar]
- Schols D., Baba M., Pauwels R., De Clercq E. Flow cytometric method to demonstrate whether anti-HIV-1 agents inhibit virion binding to T4+ cells. J Acquir Immune Defic Syndr. 1989;2(1):10–15. [PubMed] [Google Scholar]
- Schwartz O., Henin Y., Marechal V., Montagnier L. A rapid and simple colorimetric test for the study of anti-HIV agents. AIDS Res Hum Retroviruses. 1988 Dec;4(6):441–448. doi: 10.1089/aid.1988.4.441. [DOI] [PubMed] [Google Scholar]
- Sherman P. A., Fyfe J. A. Human immunodeficiency virus integration protein expressed in Escherichia coli possesses selective DNA cleaving activity. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5119–5123. doi: 10.1073/pnas.87.13.5119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spire B., Sire J., Zachar V., Rey F., Barré-Sinoussi F., Galibert F., Hampe A., Chermann J. C. Nucleotide sequence of HIV1-NDK: a highly cytopathic strain of the human immunodeficiency virus. Gene. 1989 Sep 30;81(2):275–284. doi: 10.1016/0378-1119(89)90188-1. [DOI] [PubMed] [Google Scholar]
- Stein B. S., Gowda S. D., Lifson J. D., Penhallow R. C., Bensch K. G., Engleman E. G. pH-independent HIV entry into CD4-positive T cells via virus envelope fusion to the plasma membrane. Cell. 1987 Jun 5;49(5):659–668. doi: 10.1016/0092-8674(87)90542-3. [DOI] [PubMed] [Google Scholar]
- Subra F., Mouscadet J. F., Lavignon M., Roy C., Auclair C. Inhibition of the Moloney murine leukemia virus cycle at a post reverse transcriptional step by the netropsin-intercalating hybrid molecule netropsin-oxazolopyridocarbazole. Biochem Pharmacol. 1993 Jan 7;45(1):93–99. doi: 10.1016/0006-2952(93)90381-6. [DOI] [PubMed] [Google Scholar]
- Wild C., Oas T., McDanal C., Bolognesi D., Matthews T. A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10537–10541. doi: 10.1073/pnas.89.21.10537. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yeh P., Landais D., Lemaître M., Maury I., Crenne J. Y., Becquart J., Murry-Brelier A., Boucher F., Montay G., Fleer R. Design of yeast-secreted albumin derivatives for human therapy: biological and antiviral properties of a serum albumin-CD4 genetic conjugate. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1904–1908. doi: 10.1073/pnas.89.5.1904. [DOI] [PMC free article] [PubMed] [Google Scholar]