Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.
HP 0.35, a cephalosporin degradation product is a specific inhibitor of lentiviral RNAses H.
Nucleic Acids Res. 1991 Aug 11;19(15):4059-65. Unique Identifier : AIDSLINE MED/91334109 Hafkemeyer P; Neftel K; Hobi R; Pfaltz A; Lutz H; Luthi K; Focher F; Spadari S; Hubscher U; Department of Pharmacology and Biochemistry, University of; Zurich-Irchel, Switzerland.
Abstract:
Penicillins, cephalosporins and other betalactam antibiotics are widely used antibacterial drugs. Recently it was found that some of them also have effects on proliferating eukaryotic cells (Neftel, K.A. and Hubscher, U. (1987) Antimicrob. Agents Chemother. 31, 1657-1661), and one such effect was shown to be the inhibition of DNA polymerase alpha (Huynh Do,U., Neftel, K.A., Spadari, S. and Hubscher, U. (1987) Nucl. Acids Res. 15, 10495-10506). The data suggested that degradation products of betalactam antibiotics were responsible for the inhibitory effect on DNA polymerase alpha. There is some confirmation at the structural level, since we found that penicillin binding proteins, the natural target of the cephalosporins, share amino-acid homologies to DNA polymerases and also to reverse transcriptase from HIV1 (Hafkemeyer, P., Neftel, K.A. and Hubscher, U. Meth. Find. Exp. Clin. Pharmacol. 12, 43-46, 1990). We have purified and determined the structure of one product from the cephalosporin Ceftazidim and found one molecule (HP 0.35) that did not interfere with eukaryotic cell proliferation but rather had a specific inhibitory effect on the RNase H activity of human immunodeficiency virus 1 (HIV1) and feline immunodeficiency virus (FIV) reverse transcriptases, while the DNA polymerising activity of these enzymes was not affected. RNases H from HeLa cells, calf thymus and Escherichia coli on the other hand were much less affected by HP 0.35. The inhibitory concentration of 50% (IC50) was more than 10 times lower compared to those of all cellular RNases H. We therefore tested the effect of HP 0.35 on in vitro lentivirus infection as exemplified by FIV-infection of CD(4+)-cat lymphocytes in cell culture. Under conditions where cell proliferation was absolutely unaffected, HP 0.35 was able to inhibit FIV-infection in CD(4+)-cat lymphocytes. Moreover, preincubation of these lymphocytes with HP 0.35 rendered the cells completely unsusceptible to FIV-infection. These data suggest that a degradation product of a clinically used betalactam antibiotic might represent an effective inhibitor class for lentiviral RNase H.
Keywords: Animal Cats Cattle Ceftazidime/METABOLISM/*PHARMACOLOGY Cell Division/DRUG EFFECTS Cells, Cultured CD4-Positive T-Lymphocytes/MICROBIOLOGY Endoribonucleases/*ANTAGONISTS & INHIB/ISOLATION & PURIF Escherichia coli/ENZYMOLOGY Hela Cells/ENZYMOLOGY Human HIV-1/DRUG EFFECTS/*ENZYMOLOGY Immunodeficiency Virus, Feline/DRUG EFFECTS/*ENZYMOLOGY Kinetics RNA-Directed DNA Polymerase/*ANTAGONISTS & INHIB/ISOLATION & PURIF Simplexvirus/ENZYMOLOGY Support, Non-U.S. Gov't Thiazoles/*PHARMACOLOGY Thymus Gland/ENZYMOLOGY JOURNAL ARTICLE
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Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.
