Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity

Xianting Ding1, David Jesse Sanchez2,3, Arash Shahangian2, Ibrahim Al-Shyoukh1,4, Genhong Cheng2, Chih-Ming Ho11Department of Mechanical and Aerospace Engineering, UCLA, Los Angeles, CA, USA; 2Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA; 3Department of...

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Autores principales:	Ding X, Sanchez DJ, Shahangian A, Al-Shyoukh I, Cheng G, Ho CM
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2012
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/823dd85b5bbf417a8aef48e7d2ba05d3
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spelling	oai:doaj.org-article:823dd85b5bbf417a8aef48e7d2ba05d32021-12-02T02:39:45ZCascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity1176-91141178-2013https://doaj.org/article/823dd85b5bbf417a8aef48e7d2ba05d32012-05-01T00:00:00Zhttp://www.dovepress.com/cascade-search-for-hsv-1-combinatorial-drugs-with-high-antiviral-effic-a9881https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Xianting Ding1, David Jesse Sanchez2,3, Arash Shahangian2, Ibrahim Al-Shyoukh1,4, Genhong Cheng2, Chih-Ming Ho11Department of Mechanical and Aerospace Engineering, UCLA, Los Angeles, CA, USA; 2Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA; 3Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA; 4Molecular and Medical Pharmacology Department, David Geffen School of Medicine, UCLA, Los Angeles, CA, USABackground: Infectious diseases cause many molecular assemblies and pathways within cellular signaling networks to function aberrantly. The most effective way to treat complex, diseased cellular networks is to apply multiple drugs that attack the problem from many fronts. However, determining the optimal combination of several drugs at specific dosages to reach an endpoint objective is a daunting task.Methods: In this study, we applied an experimental feedback system control (FSC) method and rapidly identified optimal drug combinations that inhibit herpes simplex virus-1 infection, by only testing less than 0.1% of the total possible drug combinations.Results: Using antiviral efficacy as the criterion, FSC quickly identified a highly efficacious drug cocktail. This cocktail contained high dose ribavirin. Ribavirin, while being an effective antiviral drug, often induces toxic side effects that are not desirable in a therapeutic drug combination. To screen for less toxic drug combinations, we applied a second FSC search in cascade and used both high antiviral efficacy and low toxicity as criteria. Surprisingly, the new drug combination eliminated the need for ribavirin, but still blocked viral infection in nearly 100% of cases.Conclusion: This cascade search provides a versatile platform for rapid discovery of new drug combinations that satisfy multiple criteria.Keywords: drug combination, HSV-1, combinatorial drug optimization, feedback system control, FSC, drug screeningDing XSanchez DJShahangian AAl-Shyoukh ICheng GHo CMDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2012, Iss default, Pp 2281-2292 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Ding X Sanchez DJ Shahangian A Al-Shyoukh I Cheng G Ho CM Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity
description	Xianting Ding1, David Jesse Sanchez2,3, Arash Shahangian2, Ibrahim Al-Shyoukh1,4, Genhong Cheng2, Chih-Ming Ho11Department of Mechanical and Aerospace Engineering, UCLA, Los Angeles, CA, USA; 2Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA; 3Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA; 4Molecular and Medical Pharmacology Department, David Geffen School of Medicine, UCLA, Los Angeles, CA, USABackground: Infectious diseases cause many molecular assemblies and pathways within cellular signaling networks to function aberrantly. The most effective way to treat complex, diseased cellular networks is to apply multiple drugs that attack the problem from many fronts. However, determining the optimal combination of several drugs at specific dosages to reach an endpoint objective is a daunting task.Methods: In this study, we applied an experimental feedback system control (FSC) method and rapidly identified optimal drug combinations that inhibit herpes simplex virus-1 infection, by only testing less than 0.1% of the total possible drug combinations.Results: Using antiviral efficacy as the criterion, FSC quickly identified a highly efficacious drug cocktail. This cocktail contained high dose ribavirin. Ribavirin, while being an effective antiviral drug, often induces toxic side effects that are not desirable in a therapeutic drug combination. To screen for less toxic drug combinations, we applied a second FSC search in cascade and used both high antiviral efficacy and low toxicity as criteria. Surprisingly, the new drug combination eliminated the need for ribavirin, but still blocked viral infection in nearly 100% of cases.Conclusion: This cascade search provides a versatile platform for rapid discovery of new drug combinations that satisfy multiple criteria.Keywords: drug combination, HSV-1, combinatorial drug optimization, feedback system control, FSC, drug screening
format	article
author	Ding X Sanchez DJ Shahangian A Al-Shyoukh I Cheng G Ho CM
author_facet	Ding X Sanchez DJ Shahangian A Al-Shyoukh I Cheng G Ho CM
author_sort	Ding X
title	Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity
title_short	Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity
title_full	Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity
title_fullStr	Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity
title_full_unstemmed	Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity
title_sort	cascade search for hsv-1 combinatorial drugs with high antiviral efficacy and low toxicity
publisher	Dove Medical Press
publishDate	2012
url	https://doaj.org/article/823dd85b5bbf417a8aef48e7d2ba05d3
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_version_	1718402299256111104

Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity

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