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Nov 08, 2012
 |  BC Innovations  |  Tools & Techniques

MuSIC by design

A Harvard Medical School and Tsinghua University team has developed a technology, dubbed MuSIC, that identifies synergistic drug pairs.1 The group showed proof of concept by finding new combinations of therapeutics for HIV, but weeding out false negatives could prove challenging.

Finding synergistic drug combinations typically involves either a hypothesis-driven approach or an unbiased pairwise combinatorial screen that uses two compounds per well. The former approach can miss unanticipated interactions between targets not thought to be mechanistically linked, whereas the latter can be too unwieldy for most academic labs.

The HMS-Tsinghua team opted for a different approach called multiplex screening for interacting compounds (MuSIC), which was able to evaluate 10 compounds per well.

The team used MuSIC to examine about 500,000 drug pairs from 1,000 FDA-approved or clinically tested drugs and showed that the technology covered all 2-drug combinations using <3% of the number of wells needed in a standard unbiased screen.

A key strategy that makes MuSIC so efficient is an algorithm that guarantees each drug pair occurs in at least one well, minimizes the number of redundant pairs and provides an arrayed compound library made up of 13,106 wells-or pools-distributed in multiple 384-well plates (see "MuSIC strategy").

Thus, the researchers could evaluate 13,106 drug pools rather than 500,000 drug pairs.

The team then used a two-part cellular assay to evaluate the pools with HIV-infected cells during early and late stages of the virus' lifecycle. Part one of the assay monitored viral infection from entry to protein translation. Part two reinforced part one and also monitored viral infection during assembly, budding and infectivity.

Based...

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