DOI: 10.1177/095632029300400503. Cellular Metabolism and Anti-Influenza Activity of 1,3,4-Thiadiazol-2-Ylcyanamide (LY217896)

Cellular Metabolism and Anti-Influenza Activity of 1,3,4-Thiadiazol-2-Ylcyanamide (LY217896)

10.1177/095632029300400503

Crossref journal-article

SAGE Publications

Antiviral Chemistry and Chemotherapy (179)

Abstract

LY217896 (1,3,4-thiadiazol-2-ylcyanamide) is a 2-substituted thiadiazole that is an effective inhibitor of influenza A and B viruses in vitro and in the mouse infection model. The in vitro anti-influenza activity of LY217896 is reversed by a 10-fold excess amount of guanine or guanosine. LY217896 (1 or 10μg ml−1) effected a selective 60% decrease in the levels of intracellular pools of GTP in MDCK cells. The extent of cytotoxicity of LY217896 is positively correlated with the amount of LY217896 metabolite formed intracellularly. A cell line, derived from parental MDCK cells, was selected for resistance to 50 ng of LY217896 per ml. Unlike parental MDCK cells, the resistant cells were able to undergo log phase replication in LY217896 (25 g ml−1) and were unable to metabolize the compound. Furthermore, LY217896 had no antiviral activity against influenza A/Ann Arbor (IC50>200μg ml−1) or vaccinia virus (IC50= 13 μg ml−1) in resistant cells. In contrast, LY217896 inhibited influenza A/Ann Arbor (IC50= 0.5 μg ml−1) or vaccinia virus (IC50= 0.13 μg ml−1) in the parental MDCK cells. A thiadiazole, with a guanidinyl group in the 2 position, and ribavirin were active in both the parental cells and resistant cells. Nicotinamide (up to 240-fold excess) did not reverse the anti-influenza activity of LY217896 in vitro or in the mouse infection model. A 10-fold excess of nicotinamide reversed the cytotoxicity of 2-aminothiadiazole but not that of LY217896.

Bibliography

Colacino, J. M., Birch, G. M., & Tang, J. C. (1993). Cellular Metabolism and Anti-Influenza Activity of 1,3,4-Thiadiazol-2-Ylcyanamide (LY217896). Antiviral Chemistry and Chemotherapy, 4(5), 271â280.

Authors 3

J. M. Colacino (first)
G. M. Birch (additional)
J. C. Tang (additional)

References 41 Referenced 7

10.1093/infdis/159.3.430
{'key': 'bibr2-095632029300400503', 'first-page': '1195', 'volume': '20', 'author': 'Ciotti M.M.', 'year': '1960', 'journal-title': 'Cancer Res'} / Cancer Res by Ciotti M.M. (1960)
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10.1128/AAC.34.11.2156
10.1056/NEJM198209023071002
10.1016/S0090-9556(25)07321-0 / Drug Metab Disp by Ehlhardt W.J. (1993)
10.1016/0042-6822(65)90273-4
10.1542/peds.80.2.275
10.1128/AAC.17.5.865
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{'key': 'bibr13-095632029300400503', 'first-page': '703', 'volume-title': 'Antimicrobial agents and chemotherapy.', 'author': 'Jackson G.G.', 'year': '1963'} / Antimicrobial agents and chemotherapy. by Jackson G.G. (1963)
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10.1001/jama.1983.03330430047028
{'key': 'bibr21-095632029300400503', 'first-page': '542', 'volume': '110', 'author': 'Mostow S.R.', 'year': '1974', 'journal-title': 'Am Rev Respir Dis'} / Am Rev Respir Dis by Mostow S.R. (1974)
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{'key': 'bibr23-095632029300400503', 'first-page': '182', 'volume': '37', 'author': 'Nelson J.A.', 'year': '1977', 'journal-title': 'Cancer Res'} / Cancer Res by Nelson J.A. (1977)
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{'key': 'bibr27-095632029300400503', 'first-page': '257', 'volume': '30', 'author': 'Scott W.J.', 'year': '1973', 'journal-title': 'J Embryol Exp Morph'} / J Embryol Exp Morph by Scott W.J. (1973)
{'key': 'bibr28-095632029300400503', 'first-page': '4827', 'volume': '48', 'author': 'Scudiero D.A.', 'year': '1988', 'journal-title': 'Cancer Res'} / Cancer Res by Scudiero D.A. (1988)
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10.1073/pnas.70.4.1174
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10.1016/0166-3542(90)90005-R

Dates

Type	When
Created	10 years, 3 months ago (May 8, 2015, 6:10 p.m.)
Deposited	3 months ago (May 27, 2025, 5:31 p.m.)
Indexed	3 months ago (May 27, 2025, 6:10 p.m.)
Issued	31 years, 10 months ago (Oct. 1, 1993)
Published	31 years, 10 months ago (Oct. 1, 1993)
Published Online	31 years, 10 months ago (Oct. 1, 1993)
Published Print	31 years, 10 months ago (Oct. 1, 1993)

Funders 0

None

BibTeX

@article{Colacino_1993, title={Cellular Metabolism and Anti-Influenza Activity of 1,3,4-Thiadiazol-2-Ylcyanamide (LY217896)}, volume={4}, ISSN={2040-2066}, url={http://dx.doi.org/10.1177/095632029300400503}, DOI={10.1177/095632029300400503}, number={5}, journal={Antiviral Chemistry and Chemotherapy}, publisher={SAGE Publications}, author={Colacino, J. M. and Birch, G. M. and Tang, J. C.}, year={1993}, month=oct, pages={271–280} }

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  "abstract": "<jats:p>LY217896 (1,3,4-thiadiazol-2-ylcyanamide) is a 2-substituted thiadiazole that is an effective inhibitor of influenza A and B viruses in vitro and in the mouse infection model. The in vitro anti-influenza activity of LY217896 is reversed by a 10-fold excess amount of guanine or guanosine. LY217896 (1 or 10\u03bcg ml<jats:sup>\u22121</jats:sup>) effected a selective 60% decrease in the levels of intracellular pools of GTP in MDCK cells. The extent of cytotoxicity of LY217896 is positively correlated with the amount of LY217896 metabolite formed intracellularly. A cell line, derived from parental MDCK cells, was selected for resistance to 50 ng of LY217896 per ml. Unlike parental MDCK cells, the resistant cells were able to undergo log phase replication in LY217896 (25 g ml<jats:sup>\u22121</jats:sup>) and were unable to metabolize the compound. Furthermore, LY217896 had no antiviral activity against influenza A/Ann Arbor (IC<jats:sub>50</jats:sub>&gt;200\u03bcg ml<jats:sup>\u22121</jats:sup>) or vaccinia virus (IC<jats:sub>50</jats:sub>= 13 \u03bcg ml<jats:sup>\u22121</jats:sup>) in resistant cells. In contrast, LY217896 inhibited influenza A/Ann Arbor (IC<jats:sub>50</jats:sub>= 0.5 \u03bcg ml<jats:sup>\u22121</jats:sup>) or vaccinia virus (IC<jats:sub>50</jats:sub>= 0.13 \u03bcg ml<jats:sup>\u22121</jats:sup>) in the parental MDCK cells. A thiadiazole, with a guanidinyl group in the 2 position, and ribavirin were active in both the parental cells and resistant cells. Nicotinamide (up to 240-fold excess) did not reverse the anti-influenza activity of LY217896 in vitro or in the mouse infection model. A 10-fold excess of nicotinamide reversed the cytotoxicity of 2-aminothiadiazole but not that of LY217896.</jats:p>",
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