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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§ One Response to New arsenic-based compound for protein inhibition

  • Judith says:

    Homeopathic doses of arsenic (arsenicum) have been used by homeopathic doctors for many years. Homeopathy should also be studied, not assumed to be invalid. There are many things we used to assume did not exist or were not “measurable” by the methods that were available at the time, but which were later proven to exist. My grandfather taught physics at Colorado University in the days before the atom was split. Just after he died, they successfully split the atom and “physics”as he knew it was changed forever.

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