In the search for new drugs, yeast rise to the occasion
Researchers have found a new way to create valuable antibodies without needing llamas. Yes, llamas.
Llamas, alpacas, camels and other members of the camelid family produce a class of antibodies that allow scientists to determine the structures of otherwise impossible-to-study proteins in the body, understand how those proteins malfunction in disease, and design new drugs that act on them.
Use of camelid antibodies, however, is not without its downsides.
First, not all investigators who need such antibodies have access to llama (or alpaca or camel) facilities. Second, while the animals aren’t harmed, vaccinating them to generate the desired antibodies is expensive, takes as long as six months per attempt, and often doesn’t work.
A team of structural biologists from the HMS Department of Biological Chemistry and Molecular Pharmacology and from the University of California, San Francisco, have now created a llama-free solution: vials of specially engineered yeast.
The yeast method can be done in a test tube in a researcher’s own lab and has a higher success rate and faster turnaround time than both llama vaccination and previous attempts to circumvent use of camelids. The yeast system has been made freely available for nonprofit use.
The active segments of camelid antibodies are often called nanobodies because they can be much smaller than regular antibodies. A llama nanobody might bind only to a particular conformation—for example, “open” or “closed”—of a particular protein. Nanobodies can also bind to challenging proteins, such as receptors that work in oily cell membranes.
Structural biologists want to find the exact nanobody that matches their protein of interest so they can lock the protein in one position and run tests to figure out its atomic structure. According to the researchers, nanobodies could make it possible to develop drugs for biological targets that antibodies are simply too big to hit.
The HMS research team has already created a library of 500 million camelid antibodies using yeast cells. Each yeast cell has a slightly different nanobody tethered to its surface, made by a slightly different piece of synthetic DNA.
McMahon C, et al., Nature Structural & Molecular Biology, March 2018