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Methyl Groups Make a Late Entrance News & views low because most people have the same low Monica Grant is in the Department of Acad. Sci. USA 113, 14294–14299 (2016). level of educational attainment. As access to Sociology, University of Wisconsin-Madison, 3. Lutz, W., Cuaresma, J. C. & Sanderson, W. Science 319, 1047–1048 (2008). schooling expands, inequality as measured Madison, Wisconsin 53706, USA. 4. Friedman, J. et al. Nature 580, 636–639 (2020). by the AID rises because the population now e-mail: [email protected] 5. Goujon, A. et al. J. Demogr. Econ. 82, 315–363 (2016). contains many people who have no education 6. Barro, R. J. & Lee, J. W. J. Dev. Econ. 104, 184–198 (2013). and many who have several years of schooling. 7. Jones, G. W. & Ramchand, D. S. J. Int. Dev. 28, 953–973 1. Marmot, M., Friel, S., Bell, R., Houweling, T. A. J. & (2016). As school enrolment becomes universal and Taylor, S. Lancet 372, 1661–1669 (2008). members of the population begin to achieve 2. Abel, G. J., Barakat, B., Samir, K. C. & Lutz, W. Proc. Natl This article was published online on 15 April 2020. similarly high levels of education, the AID declines again. From this metric, Friedman and Organic chemistry colleagues conclude that global educational inequality peaked in 2017 and is projected to decline until 2030. Methyl groups Even though this project involves an impressive volume of data, it is still limited by problems of data scarcity. Whereas some make a late entrance high-income countries, such as France and Germany, contribute more than 55 data Emily B. Corcoran & Danielle M. Schultz points to the model, the time series for many resource-constrained and small-population The addition of a methyl group to a drug molecule can greatly countries or territories are extrapolated from alter the drug’s pharmacological properties. A catalyst has fewer than 5 data points, or rely on data last been developed that enables this ‘magic methyl effect’ to be collected in or before 2008. Although the validity of the model was evaluated by check- rapidly explored for drug discovery. See p.621 ing how well its predictions matched real data across many simulations in which one subset of data had been removed, there is no way of Developing a small-molecule drug requires alters the shape of the molecule such that it assessing how well it estimates attainment iterations of building and testing new com- can readily nestle inside a targeted protein’s trajectories for places such as Malaysia, for pounds to find one that strikes the right active site, akin to how an ergonomic com- which no data were available after 2003. The balance of pharmacological properties. The puter mouse fits snugly in the palm of your authors leverage regional trends to inform process typically takes more than 10 years and hand. analyses of countries or territories for which costs billions of dollars, because, for every However, making even small adjustments to data are scarce, but the results should be 5,000 compounds made and tested, only one molecules is frequently a major undertaking, interpreted with caution. will become an approved drug1,2. Indeed, a high- one that effectively requires chemists to break The smoothed trajectories of predicted school basketball player is twice as likely to end apart the entire structure and reassemble a change in the study also hide the profound and up playing in the US professional league as any dozen or more smaller pieces for each change. often sudden impact of education policies on single compound tested in a drug-discovery Imagine how much time and money it would schooling. The authors note non linearities in programme is to become a marketed drug (see cost if adding a new window to your home the rates of change consistent with a sudden go.nature.com/2v8pnfm). One approach to required the entire house to be taken apart increase in schooling, which might result from accelerating drug discovery is late-stage func- and rebuilt from scratch. Chemists working the elimination of school fees or an increase tionalization, in which previously prepared test in drug discovery regularly have to do this with in the years of compulsory schooling. The their molecules. recent expansion of free secondary educa- “This work is a superb Late-stage functionalization has therefore tion in many lower-income countries has the emerged as a desirable approach to acceler- potential to further advance progress towards example of a symbiotic ate drug discovery5,6: much as a construction the SDG education goals, beyond what is cur- collaboration between crew saws through existing walls to insert new rently predicted by Friedman and colleagues’ academia and the windows, chemists aspire to cut through exist- model. pharmaceutical industry.” ing chemical bonds to insert new functional Ultimately, we can monitor only what we can groups into molecules. C–H functionalization, measure: we track trends in educational attain- a type of reaction that converts ubiquitous ment and in gaps between the sexes because compounds are decorated with new atoms in carbon–hydrogen (C–H) bonds in complex those are the data that exist. Socio-economic the hope of favourably adjusting their pharma- molecules into alternative functional groups, gaps in schooling are now substantially larger cological properties. On page 621, Feng et al.3 has garnered much attention for this purpose. than are gender gaps in most world regions7, report an outstanding advance towards this Feng et al. report a substantial advance in this but sufficient data on the socio-economic long-standing and historically challenging area with the design of a metal catalyst that status of students are scarce. Likewise, almost strategy. cuts through specific C–H bonds to insert three-quarters of countries have inadequate Introducing just one cluster of atoms (a methyl groups, thus allowing the magic methyl data with which to monitor progress in functional group) into a drug molecule can effect to be explored in myriad complex and learning outcomes (such as math ematics or drastically alter the molecule’s properties. For drug-like compounds. reading skills), rather than merely in years instance, adding a methyl group (CH3, one of Selective late-stage C–H functionalization of schooling (see go.nature.com/39kd4o1). the smallest functional groups) can enhance a is constantly used in nature. For example, Global commitments to inclusive and equita- compound’s binding affinity for its biological iron-based metalloenzymes known as ble quality education run the risk of failing to target more than 1,000-fold, a phenom enon cytochrome P450s (CYP450s) are omnipresent achieve their true goals when we lack the data termed4 the ‘magic methyl effect’. This is throughout the animal kingdom because of to properly track progress. because the installation of a methyl group their crucial role in regulating metabolism7,8. 592 | Nature | Vol 580 | 30 April 2020 ©2020 Spri nger Nature Li mited. All rights reserved. ©2020 Spri nger Nature Li mited. All rights reserved. F3C Manganese catalyst CF3 N N CH N 3 Mn N CH3 N N CF3 N H N H OH H H N CH3 CH CH Source of O 3 O 3 O CH3 CH3 group N F3C N N CH CH 3 + HO OH 3 CH3 Hydrogen peroxide F F F Citalopram Hemi-oxidized citalopram Methyl-citalopram Figure 1 | Late-stage methylation of biologically relevant targets. Feng intermediate (square brackets indicate that the intermediate is formed in situ 3 et al. report that a highly tuned manganese (Mn) catalyst enables methyl (CH3) and is not isolated) that is poised for reaction with a methyl-group source. The groups to be incorporated at specific sites into complex molecules, particularly reaction was used successfully on 38 biologically active molecules, including those that have structures typical of drugs. The manganese catalyst inserts an the antidepressant citalopram. It could therefore be used to rapidly explore the oxygen atom from hydrogen peroxide into the carbon–hydrogen bond that magic methyl effect — a phenomenon in which the addition of a methyl group to the human body can most easily metabolize, yielding a reactive hemi-oxidized a drug molecule greatly enhances the molecule’s pharmacological properties. The iron atom of a CYP450 binds to biologically invoking the magic methyl effect. built into the amino acids, and are therefore active molecules and triggers their meta- The challenge with this approach is that the introduced at each step of the sequence. Some bolism by inserting oxygen into C–H bonds hemi-oxidized intermediate is more readily of the groups in a target peptide are inevitably to form double carbon–oxygen (C=O) bonds, a oxidized than is the starting material — so, if installed in the first step, and can be changed type of C–H functionalization. The elaborate the oxidation reaction were a train, it would only by running the whole sequence again, but enzyme architecture around the iron centre be a non-stop service to a C=O bond. To cir- using a different amino acid at the start. tames the metal’s otherwise rampant catalytic cumvent this complication, Feng et al. tuned Feng et al. upend this norm by demon- activity, thus allowing these reactions to pro- the reaction conditions to contain the precise strating that methyl groups can be installed ceed precisely and specifically, such that only amount of catalyst and hydrogen peroxide on a tetrapeptide (a peptide built from those substrates that fit in the enzyme’s pocket needed to deliver the hemi-oxidized inter- four amino acids) at the end of the syn- are oxidized. mediate, effectively pulling the train into a thetic sequence. Further extension of this Feng and colleagues are part of a research station en route to the C=O terminus.
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