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NATURE Vol 465 20 May 2010 parasites (Toxoplasma, Leishmania and active compounds — and an earlier, partial y These reports1,2 offer tremendous opportunities trypano somes) and on replicating human cel described set8 identified in a high-throughput to develop the next generation of antimalarial lines, and found that most of the compounds screen against P. falciparum — should be a first drugs. They also sound a call for the academic were highly selective for Plasmodium. Prelimi- step. Compounds that prove to be potent in and pharmaceutical sectors to rise to the chal- nary pharmacokinetic analyses — investiga- rodent models, cheap to synthesize, safe and lenge. This should include a concerted chemical- tions related to how a compound is absorbed, unaffected by existing mechanisms of resist- genomics effort to identify the most appropriate distributed, metabolized and eliminated by the ance should also be evaluated for activity targets in the parasite. Time is of the essence. ■ body — suggested that many compounds were against other stages of the Plasmodium life David A. Fidock is in the Departments of generally suitable for further development. cycle. These include the sexual blood stage Microbiology and Immunology, and of Medicine As a proof of principle, the authors showed responsible for transmission to the mosquito (Division of Infectious Diseases), Columbia one compound to be efficacious in treating vectors, and the asymptomatic liver stage that University Medical Center, New York, malaria in a mouse model, albeit at concentra- precedes blood-stage infection. Final y, activity New York 10032, USA.
tions 25 -fold higher than the effective dose of must also be assessed against Plasmodium vivax e-mail: [email protected] chloroquine in the same animal model. — a species that, outside Africa, causes more Gamo et al.1 used GlaxoSmithKline's cases of malaria than P. falciparum and can, 1. Gamo, F.-J. et al. Nature 465, 305–310 (2010).
2. Guiguemde, W. A. et al. Nature 465, 311–315 (2010).
in-house chemical library to screen almost according to a clinical study in Indonesia9, 3. Snow, R. W., Trape, J.-F. & Marsh, K. Trends Parasitol. 17,
2 million compounds against asexual blood- cause severe, and at times fatal, disease. 593–597 (2001).
stage P. falciparum. Setting a similar threshold Innovative efforts by many organizations — 4. Eastman, R. T. & Fidock, D. A. Nature Rev. Microbiol. 7,
864–874 (2009).
of greater than 80% growth inhibition, in this notably the Medicines for Malaria Venture in 5. Feachem, R. & Sabot, O. Lancet 371, 1633–1635 (2008).
case at a cut-off of 2 micromolar, the authors Geneva, Switzerland — have in recent years 6. Dondorp, A. M. et al. N. Engl. J. Med. 361, 455–467 (2009).
identified more than 13,500 active compounds. greatly accelerated the development and licens- 8. Plouffe, D. et al. Proc. Natl Acad. Sci. USA 105, 9059–9064
Of these, 8,000 were equally active against ing of new antimalarial drugs10. But the discov- multidrug-resistant P. falciparum parasites, and ery pipeline remains woeful y thin, and there 9. Tjitra, E. et al. PLoS Med. 5, e128 (2008).
10. Wells, T. N. C., Alonso, P. L. & Gutteridge, W. E. Nature Rev. fewer than 2,000 displayed some non-selective are precious few alternatives to artemisinins. Drug Discov. 8, 879–891 (2009).
activity against a human liver-cancer cell line. Gamo and colleagues confirmed the relevance of their compounds by identifying among them several representatives of all existing anti- BIOmatERIalS
malarial drug classes (Table 1), with the excep- tion of the artemisinins, which were known to Intelligent glue
be absent from the starting library. Signifi- cantly, more than 11,000 of the new hits were previously proprietary to GlaxoSmithKline Haeshin Lee and are now made accessible to the general Spiders' webs are coated with microscopic droplets of glue, but the
research community for the first time. On the basis of their in-house annotations properties of this adhesive were unclear. It has now been found that the
of candidate human or microbial targets for glue's stretchiness underpins its role in catching flies.
more than 4,200 compounds, Gamo et al. pre- dict that many active compounds might target Man-made glues are mono-functional — their their grip under water, an environment in which kinase enzymes of P. falciparum. If confirmed, material properties are designed to stick one most adhesives function poorly.
this would constitute an important new direc- thing to another, and that's it. But in Nature Sahni and colleagues' study1 of glue droplets tion for antimalarial drug development — one Communications, Sahni et al.1 report that the on spiders' webs suggests that the coupling of that might cross paths with researchers exploit- ‘glue' droplets that coat spiders' webs are multi- adhesion with extension is a common design ing the vast chemical repositories developed functional. Depending on the rate at which they principle of natural adhesives. The droplets to target kinases in other disorders, including are extended, the droplets act either as a viscous consist of a complex mixture of glycoproteins solid-tumour cancers, inflammation, arthritis, adhesive or as a rubber-like elastic solid.
along with a variety of viscous small molecules diabetes and cardiovascular disease. Adhesive coatings are found everywhere. and salts. The role of the components of the Gamo and colleagues1 do not go as far as Think of the paint that covers wal s, cars and droplets has been difficult to prove, not least Guiguemde et al.2 in experimentally deter- ships' hulls; metals, such as gold and silver, because it is difficult to separate their properties mining potential parasite targets or reporting plated on jewellery; and dyes that change the from those of the underlying spider silk.
preliminary pharmacokinetic or pharmaco- colour of fabrics and hair. These coatings have The authors overcame this problem by dynamic data — this would be a huge task a variety of functions — paint prevents barna- immobilizing silk threads on a glass surface, for so many compounds. As such, their study cles and mussels from attaching themselves to and touching glue droplets to the threads with provides only starting points to test future ships' hul s, reducing drag on the ship and so a tiny glass probe. They then pulled the probe hypotheses concerning drug action. Nonetheless, improving fuel efficiency, whereas gold- and away at a constant speed, and measured the it is momentous that a large pharmaceutical silver-plated surfaces are anti-corrosive.
force exerted on the probe's tip as a function company has made its antimalarial drug- Yet adhesive materials in nature do much of distance from the droplet, until contact discovery data, including chemical structures, more. Mussels, for example, secrete a substance between the droplet and the probe was broken. freely available. These data are ful y search- that forms into ‘byssus threads', by which they They found that the force–distance response able through the European Bioinformatics attach themselves to rocks, shel s and even to depended on the speed with which the probe Institute's ChEMBL database7. feathers and fish skin (Fig. 1a). The threads was pulled away: rapid extensions of the glue Neither group1,2 claims to have discov- must have a high degree of elasticity, or they caused it to become highly viscous, whereas ered the next antimalarial drug. Instead, would snap under the physical impact of lash- slow extensions turned the glue into an elastic- they provide a remarkable diversity of novel ing tides. But they need the additional prop- solid-like material.
chemical structures on which to base new erty of adhesiveness, provided by a coating of This behaviour correlates well with the two antimalarial drug-discovery and development a glue-like material, to anchor the mussels in functions that the droplets perform in nature: campaigns. Comparison of these biological y place. What's more, the threads must maintain capturing prey and then retaining it. When
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0 Macmil an Publishers Limited. Al rights reserved NATURE Vol 465 20 May 2010 prey — typical y a flying insect — is captured in is evidence to suggest that the sugars found in a web, the silk rapidly extends on impact. Sahni glycoproteins are responsible for the sticki- Y.COM and colleagues' study reveals that the glue drop- ness of glues secreted by other organisms. For lets would become highly viscous under these example, the sugar N-acetyl-d-glucosamine is TOLIBRAR conditions, providing maximum adhesion to important for the adhesion of the holdfast of the effectively capture the spider's meal.
bacterium Caulobacter crescentus7. The molec- But after the prey has been captured, the ular components that cause spider-glue drop- P. KAY/PHO movement produced by its attempts to escape lets to form a rubbery solid remain unknown. causes a slow extension of the web. In this A series of studies investigating the molec- scenario, the glue droplets turn into a rubber- ular content and supramolecular assembly band-like material to prevent the unfortunate of glue droplets is therefore required.
prey from escaping (Fig. 1b). The glue drop- Sahni and colleagues' studies1 are just the tip lets secreted by spiders therefore constitute an of an enormous iceberg, as there are many other ‘intelligent' adhesive whose properties change interesting biomaterials that could be investi- TBADER/SPLI significantly depending on the extension rate gated by curious scientists — such as the adhe- LUS of the underlying silk. Needless to say, human sive flavonoid compounds found in plants, or M. technology has not been successful in producing the viscoelastic biofilms produced by microbes. such a smart adhesive material.
Future investigations will no doubt reveal their So what is the molecular basis of the secrets, and provide inspiration for the design adhesion–extension properties of naturally of advanced synthetic materials. occurring glues? In the case of the adhe- Haeshin Lee is in the Department of Chemistry, sive used by mussels, these properties derive Figure 1 Extensible and adhesive. a
Graduate School of Nanoscience and Technology , Mussels
from the presence in the glue molecules of a secrete underwater adhesive threads that are
(WCU), and the Molecular-level Interface Research repeating pair of amino acids: lysine, one of also extensible to resist pummelling by the
Center, Korea Advanced Institute of Science and the common amino acids, and 3,4-dihydroxy- tide. b, Sahni et al.1 report that the microscopic
Technology, Daejeon 305-701, South Korea.
l-phenylalanine (l-DOPA)2, which is more droplets of ‘glue' that coat spider silk are also
e-mail: [email protected] unusual. Molecules that contain extensively extensible and viscoelastic.
repeating l-DOPA–lysine motifs stick to a wide 1. Sahni, V., Blackledge, T. A. & Dhinojwala, A. Nature range of surfaces by forming various kinds of confers extensibility on the adhesive threads.
Commun. 1, doi:10.1038/ncomms1019 (2010).
2. Waite, J. H. & Tanzer, M. L. Science 212, 1038–1040 (1981).
covalent and non-covalent bonds3. Meanwhile, But in-depth knowledge of the molecular 3. Lee, H. et al. Science 318, 426–430 (2007).
metal ions in sea water infiltrate the adhesive structure of the glue droplets on spiders' webs 4. Waite, J. H., Vaccaro, E., Sun, C. & Lucas, J. M. Phil. Trans. R. Soc. Lond. B 357, 143–153 (2002).
threads, interconnecting scaffold proteins is lacking. It has been reported that the droplets 5. Vollrath, F. et al. Nature 345, 526–527 (1990).
co valently and/or by coordination4 (a pro cess contain small molecules such as neurotrans- 6. Choresh, O., Bayarmagnai, B. & Lewis R. V. in which molecules bind non-covalently to mitters, amino acids and peptides5, as wel as Biomacromolecules 10, 2852–2856 (2009).
7. Tsang, P. H., Li, G., Brun, Y. V., Freund, L. B. & Tang, J. X. metal ions). This intermolecular crosslinking macromolecules such as glycoproteins6. There Proc. Natl Acad. Sci. USA 103, 5764–5768 (2006).
takes on the relatively simple organization of Roots respond to an inner calling one central cylinder containing water-conduct-
ing xylem elements arranged in arches, which separate the nutrient-conducting phloem elements. The narrow Arabidopsis root has only a single xylem axis in which the conduct- In plant roots, patterning of two types of water-conducting xylem tissue is
ing cells specialize into central metaxylem determined by a signalling system that involves the reciprocal dance of a
(with pitted cell walls) and peripheral pro- mobile transcription factor and mobile microRNAs.
toxylem (with spiral cell wal s). It was shown previously that the transcription factor SHORT ROOT (SHR), which is expressed in the cen- Reciprocal signalling over tissue boundaries is in the context of groups of cel s that can move tral cylinder but is unable to efficiently influ- a well-known developmental feature in fruitfly relative to one another, and that need to trans- ence nuclear activity there, travels from cel embryos. Surprisingly, a similar mechanism late positional information encoded in a cell to cel , ultimately leaving the central cylinder seems to apply in the plant root, as described nucleus into cel ular positional information — and ending up in the surrounding cell layer3. by Carlsbecker and colleagues on page 316 of as in the fly embryo. There, a system that uses the physical partner Carlsbecker et al.1 show that reciprocal and downstream target of SHR, SCARECROW In fruitflies, the anterior and posterior signalling operates in the root of the model (SCR), as well as other proteins, leads to effi- parasegments, pre-specified by transcrip- plant Arabidopsis thaliana, in which, in con- cient nuclear uptake of SHR and activation of a tion factors, communicate and stabilize their trast to animals, cell positions are stable. The transcriptional pathway that specifies this cel boundaries using short-range signals carried authors reveal how a mobile transcription layer as endodermis4–6 (Fig. 1a).
by Hedgehog and Wingless — small secreted factor and mobile microRNAs perform an Carlsbecker et al.1 show that this act of inside- proteins originating from one parasegment intimate reciprocal dance to consolidate cel out signalling sets up a signalling pathway tar- and perceived by the neighbouring one. identities at the boundary between the inner geted outside-in. SHR binds directly to and These signals help to consolidate their own vascular tissue of the plant and the surrounding activates a set of microRNA genes, with the aid expression at boundaries created by earlier cell layers.
of its helper protein SCR, resulting in endoder- pattern ing systems. Moreover, they create new The vascular tissue of plants consists of mis-specific production of these small RNAs. short-range patterns with the boundary as an branched networks in leaves and separated Recently, the mobility of a member of an unre- ‘organizing centre'2. This strategy makes sense strands in stems. But in the root, the tissue lated class of small RNA, known as tasiRNAs, 0 Macmil an Publishers Limited. Al rights reserved

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