Scientists have improved protein drugs using an approach based on “ancestral sequence reconstruction,” or ASR. The newly established strategy promises to enhance the ability to engineer more efficient and durable proteins, as in the case of human factor VIII for hemophilia.
The study “Enhancing the pharmaceutical properties of protein drugs by ancestral sequence reconstruction” was published in the journal Nature Biotechnology.
The protein blood clotting protein known as factor VIII is deficient in the inherited disorder hemophilia A. Scientists began producing the recombinant human factor VIII protein in the laboratory in the early 1990s but the product still has some problems — it does not live long in the blood and it frequently stimulates immune responses from the human host. Also, the production of recombinant proteins is still technically difficult and very costly.
Experimental hematologist and gene therapist Chris Doering, PhD, and his colleagues hypothesized that looking back into the evolution of this factor could probably lead to finding a more stable form of the protein.
“We hypothesized that human factor VIII has evolved to be short-lived in the blood to reduce the risk of thrombosis,” Doering said in a press release. “And we reasoned that by going even farther back in evolutionary history, it should be possible to find more stable, potent relatives.”
To this end, Doering’s team worked closely with Trent Spencer, PhD, director of cell and gene therapy for the Aflac Cancer and Blood Disorders Center, and Eric Gaucher, PhD, associate professor of biological sciences at Georgia Tech, who specializes in ASR.
Specifically, ASR is the calculation of ancient protein sequences on the basis of the existing sequences. Researchers used this method and retrieved information on recent genome sequences from animals as varied as mice, cows, goats, whales, dogs, cats, horses, bats and elephants.
Through ASR, scientists can reconstruct a plausible ancestral sequence for a protein in early mammals. Then, they can go to the human protein and “play” with it, by changing one amino acid (the building blocks of proteins). Doing this in the direction of the ancestral protein, scientists can then assess how the step-by-step changes could affect the protein.
In the current study, the research team showed that amino acid changes toward ancestral sequences could make human factor VIII more stable and less a target for human immune system responses.
‘This exemplifies how understanding the evolutionary history of a protein can help engineer better versions of the protein for therapeutic use,” Gaucher said.
The research team concluded: “ASR is a widely accessible strategy that utilizes both known and unknown natural protein diversity to rapidly probe a protein design space that has already been refined by natural selection for beneficial properties.”
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