Organic Chemistry at the Interface to Biology Report on by azaaaaa5

VIEWS: 0 PAGES: 5

									DOI: 10.1002/cbic.200600068


Organic Chemistry at the Interface to Biology**
Rasmus P. Clausen*[a]


The continued development of new re-                Sander, to Frederik Christian Krebs from        its ability to accept hydrogen bonds.
actions, reagents and analytical tools              the Risø National Laboratory in Denmark         Again, an extensive search in the CSD re-
within organic chemistry has increased              (www.risoe.dk). Krebs was awarded for           vealed that the oxo-groups of sulfon-
the power and control of how organic                his research in polymer-based organic           ACHTUNGREamides rarely participate in hydrogen
and in particular bioorganic molecules              solar cells.                                             bonds, but rather display dipole interac-
may be transformed, modified and stud-                 In his prize lecture, Krebs stated that               tions with amide carbonyl groups; this
ied. The way researchers use synthetic              his personal mission was to put plastic                  explains why this is a popular functional
and natural chemical entities, as well as           solar cells on the market. However, sta-                 group.
the chemical modification of biological             bility and efficiency problems counteract                   Project leader from Pfizer David Price
entities, has undergone a true revolution           this, though low cost compared to con-                   gave the audience a clear impression of
to reveal mechanisms, pathways and                  ventional inorganic solar cells should be                the tremendous efforts underlying the
therapeutic interventions in a plethora             guaranteed. Initial stability problems, pri-             discovery of Maraviroc (UK-427857), an
of biological systems. Thus, an expand-             marily caused by oxygen, have now                        antagonist at the CCR5 chemokine re-
ing independent field at the interface              been solved, and the prize winner was                    ceptor that is applied in the treatment
between chemistry and biology, includ-              confident that eventually the efficiency                 of HIV infections.[3] The target was origi-
ing bioorganic chemistry, medicinal                 problem would be solved, too.[1] As later                nally established from the notion that
chemistry and chemical biology, has                 stated by Professor Shinkai, organic                     homozygous people with a mutation in
been emerging over many years.                      chemistry potentially can introduce                      the CCR5 coreceptor were resistant to
   On the 27th and 28th of January at               more variation than inorganic chemistry,                 the HIV virus, whereas heterozygotes dis-
the Falconer Center in Copenhagen,                  and therefore the potential could be                     played a delayed disease progression.
Denmark, 200 researchers from industry              greater. During the work, Krebs and co-                  Starting from a hit in a high-throughput
and academia gathered for the 4th Knud              workers devised an efficient method for                  screening, many of the problems with
Lind Larsen symposium entitled “Organic             removing Pd from their final product, a                  respect to affinity, antiviral potency,
Chemistry at the Interface to Biology” to           well-known problem for most Pd-cou-                      HERG channel activity, absorption, degra-
hear prominent researchers in the field             pling reactions.[2] The first step in putting            dation, etc. were solved through a series
present their work. These two-day sym-              solar cells on the market was a collabo-                 of functional-group interchanges, confor-
posia, held every second year by The                ration with designers to make clothes                    mational restrictions and bioisosteric ex-
Danish Academy of Technical Sciences                containing the solar cells.                              changes. And as often observed in me-
(www.atv.dk), are the most prestigious                 The symposium was opened by Pro-                      dicinal chemistry, solving one problem
international chemistry meeting in Den-             fessor Klaus Müller, from F. Hoffman–La                  creates another, but eventually they ar-
mark and cover various aspects of organ-            Roche, who discussed why benzodiaze-                     rived at Maraviroc, which had all the de-
ic chemistry. The symposium has a differ-           pines are privileged in drug develop-                    sired properties, including a very slow
ent theme each time and a tradition of              ment, and concluded that the seven-                      off-rate, which is probably necessary for
attracting very prominent speakers.                 membered carbo- and heterocyclic ring                    the drug to prohibit the initial virus
   The meeting also hosts the presenta-             structure offers privileged structures, in               binding.
tion of the Knud Lind Larsen Prize, which           general. An extensive search in the Cam-                    Professor Tom W. Muir, from the Rock-
is given to a talented young Danish                 bridge Structural Database (CSD) re-                     efeller University, has for several years
chemist. This year, the prize was present-          vealed that, depending on the number                     shown how expressed protein ligation
ed by the Danish Minister for Science,              of unsaturated bonds in the ring, various                (EPL) can be used to incorporate novel
Technology and Innovation, Helge                    stabilised conformations are obtained                    functions into natural proteins in order
                                                    that point the ring substituents in de-                  to understand crucial mechanisms and
[a] Prof. Dr. R. P. Clausen                         fined directions. Thus, the seven-mem-                   pathways.[4] The technology exploits the
    Department of Medicinal Chemistry               bered ring system, as opposed to five-                   natural extein–intein system for protein
    Danish University of Pharmaceutical Sciences    and six-membered rings, is a treasury of-                ligation, and in his lecture, several exam-
    Universitetsparken 2
                                                    fering excellent conformationally restrict-              ples convincingly displayed the power of
    2100 Copenhagen (Denmark)
    Fax: (+ 45) 3530-6040                           ed scaffolds.                                            this technique. The first application was
    E-mail: rac@dfuni.dk                               Furthermore, another privileged struc-                in the TGF-b signalling pathway, in
[**] Report on the Knud Lind Larsen Symposium.      ture, sulfonamide, was investigated for         which activation by phosphorylation of


ChemBioChem 2006, 7, 845 – 849                 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim                                                  845
the TGF-b receptor initiates the binding      fication. Professor Thomas Carell, from        with larger grooves and increased stabili-
and phosphorylation of another protein        Ludwig-Maximillians University, has for        ty due to better stacking properties of
SMAD2. This induces trimerisation of          several years been interested in how           the bases.[14] Examples of widened DNA
SMAD2, which then moves into the nu-          DNA is degraded and repaired. By syn-          and doubly expanded (naphthyl) DNA
cleus and induces further signalling          thesis and incorporation of degraded           were also demonstrated. A spectacular
events. The phosphorylation events are        bases into DNA, the repair and mutagen-        example was the exchange of bases with
essential in these signalling steps, as has   ic mechanisms can be studied. He fo-           fluorophores. By making 11 different
been evidenced by preparing phospho           cused in his talk on the two most abun-        ACHTUNGREfluorophores and combining them in tet-
variants of the proteins by using EPL.[5]     dant lesions resulting in 7,8-dihydro-8-                ramers, a plethora of fluorescence col-
By inserting a phosphorylated serine          oxoguanine (8-oxoG) and imidazole ring-                 ours was produced, some tetramers
bearing a photocleavable group into           opened purines (FapyG). A carbocyclic                   changing colour while illuminated.[15]
SMAD2, a light-induced trimerisation          analogue of FapyG (cFapyG) as well as 8-       Professor Kool then turned to shape-
event was enabled.[6] In order to follow      oxoG were crystallised in the DNA-repair       mimicking bases, such as 1,3-diflouroto-
the movement into the nucleus, the pro-       enzyme formamidopyrimidine-DNA gly-            luene (F), which was initially developed
tein was labelled with a fluorescent          cosylase (Fpg), which excises oxidised         as an iso-shape and -electronic replace-
group, and a photocleavable quencher          purines by glycosidic cleavage. Indeed,        ment for thymine (T) that lacks hydro-
was attached to a residue important for       the crystal structure shows the lesion to      gen-bonding properties and therefore
trimerisation .This created a photoindu-      have an extrahelical conformation.[11] De-     destabilises the helix when inserted. De-
cable trimerisation event in which the        spite the similarity of the two lesion         spite the lack of hydrogen-bonding
movement of the fluorescent protein to        bases, they are recognised very different-     properties, polymerase still inserts A at
the nucleus could be followed in vitro.[7]    ly by Fpg in a anti and syn conformation       the new F base with very high fidelity.
Another example was the photolabile           of the glycosidic bond, respectively.          Today there are also a number of differ-
lipidation of proteins, which created pro-    These two very different conformations         ent nonpolar bases that have been
teins that move from the membrane to          are accepted because the binding site is       shown to be incorporated by poly-
the cytoplasm when irradiated. While          very open; this also explains why so           merase, and, in the series of 1,3-dihalo-
these applications were performed in          many different lesions are substrates for      benzenes, the chloro-substituted com-
vitro, the most spectacular was the           the enzyme, but why normal bases are           pounds were incorporated with the
whole-animal application. This involves       not excised is still unresolved. Perhaps       highest efficiency and fidelity.[16] Evident-
the use of conditional protein splicing[8]    more interestingly, these lesion bases         ly, the natural replication system allows
in which two fragments of luciferase          were used for studying their contribu-         for a surprisingly large variation in the
were lengthened with two fragments of         tion to mutagenesis. X-ray crystal struc-      system; this gives hope that it will even-
a split intein followed by the classical      tures of a polymerase fragment revealed        tually be possible to invent a novel repli-
FKBP-FRB pair, which dimerises upon the       that 8-oxodG is recognised in the syn          cating system.
addition of rapamycin. These two hybrid       conformation; this leads to “mismatch”                              Professor Peter Dervan, from the Cali-
proteins can be expressed in a fruit fly      pairing with A and thereby mutations.[12]      fornia Institute of Technology, left the
so that, upon administration of rapamy-       cFapyG does not create similar mis-            DNA molecules intact and focused on
cin, luciferase is produced and together      match, but still affects the fidelity in the   small molecules that bind to DNA and
with luciferin light is emitted. Thus, a      polymerase reaction. Carell also showed        thereby prevent gene expression. The
fruit fly is turned into a “fire fly”.        how the UV-induced cis–syn cyclobutane         lead structure was distamycin, one of
   Professor Mikael Bols, from the Univer-    pyrimidine dimers (CPDs) are repaired by       several DNA-binding natural products,
sity of Aarhus, presented his recent work     light-excited FADH in DNA photolyases,         which contains an N-methylpyrroleamide
on cyclodextrin-based artificial enzymes,     again based on X-ray crystal struc-                     oligomer that binds to A–T-rich minor
which was initially inspired by the hydro-    tures.[13]                                              grooves. Exchanging the pyrrole with
lytic mechanism in glycosidases involv-          Whereas Carell discussed naturally oc-               imidazole or 3-hydroxypyrrole gives two
ing two carboxylic acid groups. However,      curring alternative DNA bases, Professor                additional base binders. Hairpin poly-
the cyclodextrin containing two acidic        Eric T. Kool, from Stanford University,                 ACHTUNGREamide dimers containing these three
groups was not the most efficient in cat-     made unnatural changes to the hetero-                            heterocycles afford a small-molecule rec-
alysing the cleavage of a nitrophenol         cyclic part of DNA bases to introduce                            ognition code that discriminates among
glycoside, but a biscyanohydrin-substi-       benzofusions and substitution with fluo-                         all four Watson–Crick base pairs in the
tuted cyclodextrin.[9] He also showed an      robenzene. The overall goal is to estab-                         minor groove.[17] It is easy to envision
example of a very simple, but highly effi-    lish replicating systems with novel prop-      the therapeutic prospects of this tool,
cient, hydrogen peroxide oxidation cata-      erties. First, examples of DNA bases           but one premise would be that the mol-
lyst in which a bridged ketone was incor-     whose size had been increased by inser-        ecules not only enter the cell but also
porated into the cyclodextrin.[10]            tion of a fused benzo-group were               the nucleus. Dye-linking of the com-
   Although the context of the symposi-       shown. Whereas insertion of a single ex-       pounds showed that this was the
um was very broad, several of the talks       panded base led to decreased stability,        case.[18] Another issue was the stability of
dealt with various aspects of DNA modi-       the exchange of all pairs led to a duplex      the compounds, and the bioisosteric ex-


846         www.chembiochem.org                2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim               ChemBioChem 2006, 7, 845 – 849
change of the pyrrolamide to benzimid-                                 DNA. Thus, silica tubes, rods and dough-                                Subsequently, they tried to identify the
ACHTUNGREazole along with similar exchanges of                         nuts with DNA inside were formed in a                                   target of the compounds. This illustrates
         the other heterocyclic codes indeed pro-                      conACHTUNGREtrolled manner.[22]                                         an example of a late-stage multiple-
         vided more stable compounds with con-                                                       The second idea involved polymeri-        target screening.
         served recognition properties.[19] More-                      sation of an organic material around a                                              Professor Matthew D. Shair, Harvard
                           over, a direct application to hypoxia-      template. By using stacks of porphyrin-                                 University, shared further examples of
                           induced angiogenesis as an antitumor-       ACHTUNGREtetrasulfonates, fullerenesulfonates and                       phenotype screening from his research,
                           growth strategy was demonstrated.[20]                DNA as templates, conductive thiophene                         which focuses on the secretory pathway.
         Hypoxic conditions induce transcription                                and pyrrole polymers can be formed in a                        Inspired by the widespread use of brefel-
         of vascular endothelial growth factor                                  controlled manner.[23] One example was                         din A as a powerful tool for studying this
         (VEGF) through the binding of a hetero-                                                  the use of singe-walled carbon nano-         pathway, his team decided to look for
         dimeric protein complex (HIF-1a/ARNT)                                                    tubes (SWNT) complexed with DNA as           similar compounds that act at other
         to a specific DNA sequence. Dervan and                                                   templates, here the negative phospho-        stages in this pathway. In a phenotypic
         co-workers demonstrated that the addi-                                                   nate charges attract the positive charges    screening of a biomimetic diversity-ori-
         tion of a complementary hairpin dimer                                                    developed at thiophene in the oxida-         ented synthetic galanthamine-like library
         suppressed the expression of this gene                                                   tion–polymerisation process. Interesting-    of 2527 compounds, they discovered
         and thereby VEGF levels.                                                                 ly, photoexcitation of ethidium bromide      secramine as a potent inhibitor of VSVG-
                             Examples of templated self-assembling                                inside this polymer generates a photo        GFP movement from the Golgi apparatus
         dimers from “click-chemistry” were pre-                                                  current, thus indicating the potential ap-   to the plasma membrane.[25] This rapid
         sented as well as the addition of further                                                plication of such a material.                         discovery led to 41=2 years’ work to iden-
         structural elements. The latter enabled                                                     The third idea centred on the use of a             tify the compounds’ biological target.[26]
         the incorporation of various functions,                                                  1D cavity as a template. Shinkai and co-     They found that secramine inhibits acti-
         such as the recruitment of other pro-                                                    workers have found that b-1,3-glucan         vation of Rho GTPase Cdc42, a protein
         teins; this extends the possibilities in this                                   polysaccharides have triple-stranded he-              involved in membrane traffic, possibly
         elegant technique and reminds us how                                            ACHTUNGRElical structures that are excellent 1D       by stabilising its association with the
         “synthetic chemistry is the discovery and                                                hosts for a number of applications, such     guanine dissociation inhibitor RhoGDI1,
         invention of new properties”.                                                            as the complexation and inclusion of         thus the compound is a protein–protein
                             Professor Seiji Shinkai, Kyushu Univer-                              SWNTs, polythiophenes, etc.[24]              interaction stabiliser. From another li-
         sity, also uses DNA in his work, but as a                                                   Thus, Shinkai demonstrated that nano-     brary, they have recently identified a
         template rather than a target. He pre-                                 materials can be produced in a con-                            compound called Dispergo that induces
         dicted that in the 21st century chemists                               ACHTUNGREtrolled manner by the fusion of chemis-               dispersion of the Golgi apparatus. No-
         would eventually win over physicists in                                         try and biology and that these materials              ACHTUNGREcodazole similarly disperses the Golgi ap-
         the miniaturisation race. The bottom-up                                         may be applied in the areas of “biotech,                       paratus but the three layers in the Golgi
         approach exemplified in the supramolec-                                         nanotech and infotech”.                                        apparatus are conserved, whereas Dis-
         ular field is easier, more variable and                                                     Speakers from the medical industry                 pergo is the first compound that also
         offers more control than the top-down                                           are often unable to show the chemical                          splits the layers thus simulating the dis-
         approach offered by engineering physi-                                          structures of active compounds from                            persion that happens during mitosis. Dis-
         cists, thus pointing to a greater poten-                                        their research for obvious reasons. How-                       pergo therefore provides a tool for
         tial. Shinkai presented three ideas; the                                        ever, it was unusual that Ole Thastrup,                        studying mitosis-like events and in
         first could be considered a combination                                         Head of Biosector, Carlsberg Research                          recent studies they found that Golgi can
         of the chemists’ and physicists’ ap-                                            Center, in his lecture showed neither                          reassemble independent of the endo-
         proaches, grafting on organic materials                                         chemical structures nor the entities they                      plasmatic reticulum. Shair’s examples
         like DNA on a molecular level by silica                                         targeted. He did, though, present an ex-                       showed clearly the potentials of pheno-
         formation. His first examples were on                                           ample of an interesting and increasingly                       typic screening.
         positively charged cholesterol derivatives                                      popular approach in which compounds                               Associate Professor Poul Nissen, Uni-
         that form chiral helices. Due to its                                            are screened for phenotype instead of                          versity of Aarhus, presented a movie
         ACHTUNGREnegative charge, the silica polymerises                                against a single isolated target. Thastrup                     called “Pump Fiction” which showed a
                  around the positive charges, replicating                               and co-workers have developed a tech-                          cartoon of how the sarco-endoplasmic
                  the chiral shape of the cholesterol heli-                              nique in which living cells are anchored                       reticulum calcium ATPase (SERCA)
                  ces and giving a material that can be                                  on resin beads via d-amino acids togeth-                       pumps calcium ions across the cell mem-
                  used as a chiral catalyst or just miniatur-                            er with compounds synthesised in a                             brane. SERCA belongs to the family of P-
                  ised silica pasta.[21] DNA was also used                               combinatorial fashion attached via a                           type ATPases, which has its own history
                  as template. DNA is negatively charged,                                photolabile linker, and could identify                         at the University of Aarhus, since the
                  so a proper spacer having positively                                   compounds that potentiate STS-induced                          first member of this family, Na + ,K + -
                  ACHTUNGREcharged guanidinium and ammonium                              apoptosis. By taking both healthy and                          ATPase, was discovered there by Nobel
                           groups at each end was added in order                         diseased cells from a cancer-infected                          Laureate Jens-Christian Schou. Nissen’s
                           to give an overall positive charge to                         colon, they identified Taxol potentiators.                     movie was produced by morphing sever-


ChemBioChem 2006, 7, 845 – 849                              2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim                                        www.chembiochem.org                    847
al X-ray structures from Toyoshima and          the thrombin-binding part of heparin.            as Dervan also exemplified. The initial
Nissen’s laboratories of different states of    However, Arixtra is still more effective as      synthetic challenges in this development
SERCA.[27] These crystal structures repre-      an antithrombotic and has fewer side ef-         make the story even more impressive.
sent different intermediate and transition      fects than heparins; thus it was quickly            In conclusion, this meeting gave an
states captured by the addition of both         approved after phase III clinical trials. In     excellent overview of the many different
organic and inorganic compounds, such           the first synthesis it was produced on a         and exciting techniques developed by
as the natural product inhibitor Thapsi-        milligram scale, but later more than 20 g        the use of organic chemistry for modify-
gargin or the phosphoryl transfer mim-          was made for toxicological studies and           ing, exploiting and investigating nature’s
icker aluminium tetrafluoride, to arrest        initial clinical trials. In the year 2000, the   own biological molecules and, more im-
the protein in specific states. The struc-      total production was 8 kg. The strong            portantly, the interaction between them.
tures reveal the molecular basis for the        binding to AT-III prevents the degrada-          These lectures showed how organic
coupling of ATP hydrolysis to the calci-        tion of Arixtra, so its half-life is 17 h. The   chemistry and biology continue to
um transport event by conformation              compound was further developed, and              merge, detailing what turned out to be
changes of the protein. They also reveal        the synthesis 150 different derivatives          an outstanding two-day journey through
how a leak is avoided by complete oc-           enabled identification of essential func-        the picturesque landscape at the inter-
clusion of calcium and how occluded             tional groups, thus resulting in a modi-         face between chemistry and biology.
transition states of calcium transport and      fied compound Idraparinux with an extra
proton countertransport are coupled to          sulfate group and N-sulfate groups ex-
                                                                                                   [1] F. C. Krebs, H. Spanggaard, Chem. Mater.
phosphorylation and dephosphorylation,          changed with O-sulfate groups. This in-
                                                                                                       2005, 17, 5235.
respectively.                                   creased the potency and increased the              [2] K. T. Nielsen, K. Bechgaard, F. C. Krebs, Macro-
   Director Jesper Lau from Novo-Nordisk        half-life to 170 h, meaning that this com-             molecules 2005, 38, 658.
presented some general aspects of post-         pound can be given once a week instead             [3] P. Dorr, M. Westby, S. Dobbs, P. Griffin, B.
                                                                                                       Irvine, M. Macartney, J. Mori, G. Rickett, C.
translational modifications, which they         of once a day. Furthermore, the number
                                                                                                       Smith-Burchnell, C. Napier, R. Webster, D.
apply to insulin to improve the proper-         of steps in the synthesis of the com-                  Armour, D. Price, B. Stammen, A. Wood, M.
ties of this therapeutic protein. There are     pound was also reduced.                                Perros, Antimicrob. Agents Chemother. 2005,
several reasons and ways to engineer               Organon was interested in developing                49, 4721.
                                                                                                   [4] T. W. Muir, Ann. Rev. Biochem. 2003, 72, 249.
proteins, but the primary reason is often       these pentasaccharides into antithrom-
                                                                                                   [5] M. Huse, T. W. Muir, L. Xu, Y.-G. Chen, J. Kuriy-
to increase stability, thereby avoiding         bins; this requires the presence of the                an, J. Massagu, Mol. Cell 2001, 6, 671; J. J. Ot-
fast clearance. One of the more popular         thrombin interacting end (TBD) of the                  tesen, M. Huse, M. D. Sekedat, T. W. Muir, Bio-
approaches has been to introduce poly-          heparin hexadecasaccharide. The TBD                    chemistry 2004, 43, 5698.
                                                                                                   [6] M. E. Hahn, T. W. Muir, Angew. Chem. 2004,
(ethylene glycol) (PEG) to amino acid           binding end could be mimicked by a
                                                                                                       116, 5924; Angew. Chem. Int. Ed. 2004, 43,
side chains to improve one or several           simple sulfated trisaccharide. Thus, the               5800.
properties, such as decreased renal clear-      AT-III binding end (ABD) was attached to           [7] J.-P. Pellois, M. E. Hahn, T. W. Muir, J. Am.
ance, solubility, bioavailability, and re-      the TBD via spacers of varying lengths                 Chem. Soc. 2004, 126, 7170.
                                                                                                   [8] H. D. Mootz, E. S. Blum, A. B. Tyszkiewicz,
duced antigenicity. As a case history, Lau      and nature. Initially, PEG-type linkers
                                                                                                       T. W. Muir, J. Am. Chem. Soc. 2003, 125,
showed how the half-life of the GLP-1           were used, but later neutral oligosac-                 10 561.
derivative Liraglutide was increased by         charides were applied; this reduced the            [9] F. Ortega-Caballero, C. Rousseau, B. Christen-
enhanced binding to albumin by the ad-          flexibility of the linker and thereby the              sen, T. E. Petersen, M. Bols, J. Am. Chem. Soc.
                                                                                                       2005, 127, 3238.
dition of palmitoyl side chains. By engi-       entropic loss in affinity. An advantage of
                                                                                                 [10] L. Marinescu, M. Molbach, C. Rousseau, M.
neering GLP-1, the half-life was increased      the linking approach is the removal of                 Bols, J. Am. Chem. Soc. 2005, 127, 17 578.
from 2 min to 130 h.                            charged groups between ABD and TBD,              [11] F. Coste, M. Ober, T. Carell, S. Boiteux, C.
   Most companies would probably close          which in heparin are involved in the                   Zelwer, B. Castaing, J. Biol. Chem. 2004, 279,
                                                                                                       44 074.
a project if the final drug had to be           binding of platelet factor IV and cause a
                                                                                                 [12] G. W. Hsu, M. Ober, T. Carell, L. S. Beese,
made by 60 synthetic steps. Neverthe-           potentially lethal side reaction. But Orga-            Nature 2004, 431, 217.
less, this was not the case with Arixtra,       non also undertook another approach in           [13] A. Mees, T. Klar, P. Gnau, U. Hennecke,
which was developed as an antithrom-            which the pentasaccharide was conju-                   A. P. M. Eker, T. Carell, L.-O. Essen, Science
                                                                                                       2004, 306, 1789.
botic agent to be applied during surgery        gated to a small-molecule thrombin in-
                                                                                                 [14] J. Gao, H. Liu, E. T. Kool, J. Am. Chem. Soc.
and which was developed by Professor            hibitor, NAPAP, to improve this com-                   2004, 126, 11826.
Stan van Boeckel and co-workers from            pound by preventing thrombin forma-              [15] J. Gao, S. Watanabe, E. T. Kool, J. Am. Chem.
N. V. Organon, Netherlands. The com-            tion. This compound acts at both AT-III/               Soc. 2004, 126, 12 748.
                                                                                                 [16] T. W. Kim, J. C. Delaney, J. M. Essigmann, E. T.
pound is the methylglycoside of a penta-        Xa and thrombin and is therefore a dual-
                                                                                                       Kool, Proc. Natl. Acad. Sci. USA 2005, 102,
saccharide with several O- and N-sulfate        action antithrombotic. This outstanding                15 803.
groups that is the part of heparin that         endeavour, which seems to continue               [17] C. L. Kielkopf, S. White, J. W. Szewczyk, J. M.
binds to antithrombin III (AT-III).[28] Bind-   endlessly, demonstrates how additional                 Turner, E. E. Baird, P. B. Dervan, D. C. Rees,
                                                                                                       Science 1998, 282, 111.
ing of Arixtra to AT-III induces the activa-    properties can be added to a compound
                                                                                                 [18] T. P. Best, B. S. Edelson, N. G. Nickols, P. B.
tion of factor Xa but does not induce an-       with one type of activity leading to                   Dervan, Proc. Natl. Acad. Sci. USA 2003, 100,
tithrombin activity, since this requires        tailor-made profiles in the compounds,                 12 063.


848          www.chembiochem.org                 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim                ChemBioChem 2006, 7, 845 – 849
[19] D. Renneberg, P. B. Dervan, J. Am. Chem. Soc.      [24] K. Sakurai, K. Uezu, M. Numata, T. Hasegawa,              H. Nomura, Nature 2002, 418, 605; T. L.-M.
     2003, 125, 5707.                                        C. Li, K. Kanekoc S. Shinkai, Chem. Commun.               Sørensen, J. V. Møller, P. Nissen, Science 2004,
[20] B. Z. Olenyuk, G.-J. Zhang, J. M. Klco, N. G.           2005, 4383; M. Numata, M. Asai, K. Kaneko,                304, 1672; C. Toyoshima, T. Mizutani, Nature
     Nickols, W. G. Kaelin, Jr., P. B. Dervan, Proc.         A.-H. Bae, T. Hasegawa, K. Sakurai, S. Shinkai,           2004, 430, 529; C. Toyoshima, H. Nomura, T.
     Natl. Acad. Sci. USA 2004, 101, 16 768.                 J. Am. Chem. Soc. 2005, 127, 5875.                        Tsuda, Nature 2004, 432, 361; C. Olesen, T. L.-
[21] J. H. Jung, Y. Ono, S Shinkai, Angew. Chem.        [25] H. E. Pelish, N. J. Westwood, Y. Feng, T. Kirch-          M. Sørensen, R. C. Nielsen, J. V. Møller, P.
     2000, 112, 1931; Angew. Chem. Int. Ed. 2000,            hausen, M. D. Shair, J. Am. Chem. Soc. 2001,              Nissen, Science 2004, 306, 2251.
     39, 1862.                                               123, 6740.                                           [28] M. de Kort, R. C. Buijsman, C. A. A. van Boeck-
[22] M. Numata, K. Sugiyasu, T. Hasegawa, S.            [26] H. E. Pelish, J. R. Peterson, S. B. Salvarezza, E.        el, Drug Discovery Today 2005, 10, 769.
     Shinkai, Angew. Chem. Int. Ed. 2004, 116,               Rodriguez-Boulan, J.-L. Chen, M. Stamnes, E.
     3341; Angew. Chem. Int. Ed. 2004, 43, 3279.             Macia, Y. Feng, M. D. Shair, T. Kirchhausen,
[23] T. Hatano, A.-H. Bae, K. Sugiyasu, N. Fujita, M.        Nature Chem. Biol. 2006, 2, 39.
     Takeuchi, A. Ikeda, S. Shinkai, Org. Biomol.       [27] J. V. Møller, P. Nissen, T. L.-M. Sørensen, M.
     Chem. 2003, 13, 2343; A.-H. Bae, T. Hatano,             Maire. Curr. Opin. Struct. Biol. 2005, 15, 387;
     N. Nakashima, H. Murakami, S. Shinkai, Org.             C. Toyoshima, M. Nakasako, H. Nomura, H.             Received: February 21, 2006
     Biomol. Chem. 2004, 8,1139.                             Ogawa, Nature 2000, 405, 647; C. Toyoshima,          Published online on March 10, 2006




ChemBioChem 2006, 7, 845 – 849                 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim                        www.chembiochem.org                      849

								
To top