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


CONCLUSIONS
This cascade search provides a versatile platform for rapid discovery of new drug combinations that satisfy multiple criteria.
Department of Mechanical and Aerospace Engineering, UCLA, Los Angeles, CA, USA.
Xianting
X
Ding
David Jesse
DJ
Sanchez
Arash
A
Shahangian
Ibrahim
I
Al-Shyoukh
Genhong
G
Cheng
Chih-Ming
CM
Ho
D000465:Algorithms; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D004338:Drug Combinations; D055808:Drug Discovery / Q000379:methods*; D005246:Feedback; D006561:Herpes Simplex / Q000188:drug therapy* / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells
D000998:Antiviral Agents; D004338:Drug Combinations