Science Concentrates DRUG DISCOVERY
INORGANIC CHEMISTRY
loops, and disulfides—by predicting folded shapes likely to interact with known target sites on hemagglutinin or botulinum toxin. The researchers used Rosetta to evaluate the resulting mini proteins’ binding properties. Then they synthesized DNAs that code for about 10,000 of the best designs and inserted the DNAs into yeast, which expressed the corresponding proteins on their surfaces. The scientists screened the yeast experimentally to see which of the proteins displayed on their surfaces bound most tightly to the flu and botulinum targets. The researchers then sequenced those proteins and fed information about them back into Rosetta to improve the software’s predictive ability. Two iterations of this design process yielded 14 flu and botulinum inhibitors. These mini proteins are easier to design and synthesize, more heat stable, and potentially less immunogenic than antiflu antibodies, such as those used Crystal structure shows the way mini protein HB1.6928.2.3 (orange experimental structure in vaccines. But the mini proteins and green computationally designed structure) aren’t orally available like many small-molecule drugs and are a long interacts with a key binding site on the way from being clinical candidates. hemagglutinin flu protein (cream and yellow). Many drug discovery efforts have used high-throughput screening, “while underlying prediction algorithms can be the advantages of computational methods improved over time, whereas screening is have largely been overlooked,” but the new essentially random. study and others suggest that computer deDavid Baker of the University of Washsign is coming to fruition, comments comington and coworkers demonstrated the potential of this new approach by designing putational biologist Philip M. Kim of the University of Toronto. For example, last therapeutic “mini proteins,” each containyear, Kim’s group designed 6,000 variants ing about 40 amino acids (Nature 2017, of an existing protein computationally and DOI: 10.1038/nature23912). In cell culture screened them to find nanomolar inhibiexperiments, the proteins inhibited hemagtors of a target enzyme (Sci. Adv. 2016, DOI: glutinin and botulinum neurotoxin B, the 10.1126/sciadv.1600692). cause of botulism. And one mini protein, The Baker study “is an important applicalled HB1.6928.2.3, prevented flu infection cation of high-throughput mini protein dein mice when administered by inhalation sign, selection, and production for discovwithin 72 hours of exposure to the virus. ering novel therapeutics,” says structural Baker and coworkers, including Aaron bioinformatics specialist Gaetano T. MonChevalier, Daniel-Adriano Silva, and Gatelione of Rutgers University. Structures of briel J. Rocklin, used the group’s computer mini proteins bound to their targets could software, Rosetta, to design nearly 23,000 now be used for the rational design of even mini proteins, about 100 times as many as better small-molecule, macrocyclic, or opin previous de novo protein design studies. timized mini-protein drug candidates, he Rosetta assembled the mini proteins from suggests.—STU BORMAN component parts—α-helices, β-sheets, Scientists have used a computational method to design brand-new small proteins that inhibit specific therapeutic targets such as the hemagglutinin protein involved in flu infection. The findings suggest that this method—de novo protein design—could be a wave of the future for drug discovery. Researchers often find drugs by screening large collections of compounds for those that happen to hit biological targets. Using computers to intentionally design compounds to hit targets is a newer and less proven strategy. A key advantage of this route to drug discovery is that its
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C&EN | CEN.ACS.ORG | OCTOBER 2, 2017
Periodate—an ion composed of iodine, oxygen, and hydrogen—was studied in water-based solutions extensively from the 1950s to the 1980s. Ever since those studies, chemists have accepted that periodate exists in solution as orthoperiodate (H5IO6) and metaperiodate (IO4–) species in equilibrium with each other, along with a dimer (H2I2O104–). Periodate is a strong oxidizing agent that today finds use in many synthetic strategies, including C–H functionalization and iodination. Recently, a team led by Attila K. Horváth of the University of Pécs decided to study periodate equilibria again after finding that periodate reactions run in their lab didn’t align with the literature. Horváth and colleagues’ conclusion: Orthoperiodate actually exists in aqueous solution with its three successively deprotonated siblings—H4IO6–, H3IO62–, and H2IO63– (Inorg. Chem. 2017, DOI: 10.1021/acs. inorgchem.7b01911). They did not find any evidence for metaperiodate or the dimer. The team studied periodate equilibria through gravimetric analysis, potentiometry, ultraviolet absorption spectroscopy, and Raman spectroscopy—recreating literature experiments and adding new ones, investigating the effects of different electrolytes, controlling for pH, and staying within periodate’s solubility range. In the end, the researchers’ results align with those reported by Carl E. Crouthamel and coworkers in the 1950s (J. Am. Chem. Soc. 1951, DOI: 10.1021/ja01145a030). Clarifying periodate’s composition in aqueous solution may contribute to a better understanding of the role its various species play in chemical processes, Horváth and colleagues say.—JYLLIAN KEMSLEY
C R E D I T: NAT UR E
Computational method yields For periodate, therapeutic ‘mini proteins’ a return to Small proteins prevent flu infection in mice and block botulinum toxin in cells the 1950s
