The authors selected 1,000 test compounds from two commercially available drug libraries and from the US National Institutes of Health's clinical compound collection. The design of the MuSIC screen was based on a heuristic algorithm to cover all the possible pairwise combinations (that is, ∼500,000 drug pairs) of these compounds. The initial assay used forty-five 384-well plates, each containing a pool of 10 compounds per well (this was <3% of the number of wells needed in a standard pairwise screen). The screen measured HIV infectivity and was designed to detect effects on both the early and late stages of the HIV life cycle.
An initial primary screen identified 288 drug pools based on low infection rate and low cytotoxicity, which were then disseminated into 12,904 drug pairs. These drug pairs were subjected to a secondary screen (another heuristic algorithm was used to design the layout of the plates), which identified 104 drug pairs that reduced the HIV infection rate by ≥50%. Two established models were then used to measure synergy between the identified drug pairs: the Bliss independence model and higher single activity model. Forty-one drug pairs were synergistic using both models. The top-ranked pair included the glucocorticoid betamethasone (which is known to reduce HIV transcription) and the antiprotozoal drug nitazoxanide (whose anti-HIV activity has not been previously reported). Other high-ranked compounds included glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs) and anticholinergic drugs.
This is a preview of subscription content, access via your institution
