Thalidomide’s molecular actions revealed

July 16, 2014 § Leave a comment

Once shunned for causing severe birth defects in babies, thalidomide has made a comeback to treat some blood cancers and leprosy. In a paper now out in Nature, researchers describe the crystal structure of the drug bound to its target. From their data, the researchers provide an explanation how this drug can either save or wreck lives.

In the 1950s, women in Europe and other parts of the world were given the sedative thalidomide to battle morning sickness. But shortly thereafter, physicians realized that drug, which was marketed by a German company, caused limb deformities and other developmental problems in children. In 1961, the drug was withdrawn from the market. Nicolas Thomä at Friedrich Miescher Institute for Biomedical Research in Switzerland says that the notorious side effects of thalidomide were impossible to ignore when he was a child. “Born in Germany in the 1970s, I saw the teratogenic side effects of thalidomide,” he says. “I come from a small community and grew up with children who were directly affected by the drug.”

So in 2010, when another group of researchers demonstrated that thalidomide binds to a protein that’s part of a ubiquitin ligase complex, Thomä was doubly intrigued. His group long has been interested in ubiquitin ligases. Furthermore, conventional thinking had dictated to date that ubiquitin ligases couldn’t be targeted by drugs. But here was thalidomide, binding to a protein called CRBN. CRBN is a ubiquitously expressed protein that is part of a family of ubiquitin ligase complexes called CRL4; mutations in CRBN are associated with mental retardation. In 1998, the U.S. Food and Drug Administration approved the use of the drug to treat skin lesions caused by leprosy; in 2006, the agency extended its approval of thalidomide to treat multiple myeloma.

Thomä and his colleagues got down to work of figuring out how thalidomide interacted with CRBN. “As often is the case in crystallography, it took the right construct, the right conditions and a little bit of luck,” says Thomä, to get the structures of thalidomide and drugs like it bound to a complex of chicken CRBN (the chicken version closely resembles the human one) and its adaptor protein.

The investigators showed that when thalidomide bound to CRBN the protein was prevented from binding to one of its targets, the homeobox transcription factor MEIS2. However, when CRBN was bound with thalidomide the protein was able to associate with a different class of transcription factors, called Ikaros. In short, thalidomide was able to divert the CRBN’s function to new substrates like Ikaros at the cost of losing MEIS2 and possibly other native substrates. Thomä stresses that the investigators still don’t know which substrate causes thalidomide’s ugly side effects.

Overall, the investigators concluded that “thalidomide simultaneously acts as antagonist and agonist on CRL4, something that was previously unanticipated,” says Thomä. “The unexpected complexity of thalidomide action, acting simultaneously as inhibitor and agonist on the ubiquitin ligase, provides a molecular framework for how small molecules can be used as drugs to up- or downregulate cellular targets.”

New arsenic-based compound for protein inhibition

February 12, 2013 § 1 Comment

The enzyme disulfide isomerase’s two pairs of vicinal thiols are about to interact with an unfolded protein has arsenical maleimide moeities attached to it. Image provided by Colin Thorpe.

The enzyme disulfide isomerase’s two pairs of vicinal thiols are about to interact with an unfolded protein has arsenical maleimide moeities attached to it. Image provided by Colin Thorpe.

Over the past two decades, arsenic-based compounds have been under investigation in clinical trials as possible therapeutics for leukemias and solid tumors. However, the current cohort of compounds is rather limited. In a recent Journal of American Chemical Society paper, researchers demonstrated a new type of arsenic-based compound that inhibits a wide range of proteins involved in disease processes.

Arsenic-based chemistry for disease treatment goes back to the early 1900s but fell by the wayside with the rise of antibiotics and other medicines in the 1940s. But there has been renewed interested in arsenic-based compounds for cancer therapies; indeed, the U.S. Food and Drug Adminstration approves the use of arsenic trioxide to treat acute promyelocytic leukemia. 

But rather than synthesizing arsenic-based compounds for specific diseases, which isn’t an efficient use of time and labor, Colin Thorpe and Aparna Sapra at the University of Delaware wondered if they could make new tools for producing arsenic-based compounds. “We wanted a versatile approach that could be easily implemented with one simple arsenical that could be quickly coupled to a wide range of peptide or protein scaffolds,” says Thorpe.

So they developed arsenical-maleimide, a simple compound that appears to quickly and efficiently attack a range of proteins and peptides that have exposed thiol (-SH) groups on them. The maleimide component of the compound latches onto one set of -SH groups. Then the arsenic, which is a good chelator of exposed thiol groups, binds to any other pairs of thiol groups that may be in the vicinity.

The investigators showed by using model peptides that they could get anywhere from one to eight molecules of arsenical-maleimide onto a chain, depending on the number of exposed thiol groups it contains. Because proteins interact with each other, proteins that had arsenical-maleimide attached to them carried the compound to their binding partners and specifically inhibited them through the arsenic moiety. “We hope that the renewed interest in arsenicals by a number of research groups might contribute to a renaissance in the use of arsenic-based therapies,” says Thorpe.

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