Key Points
-
Interfacial inhibitors belong to a broad class of natural products and synthetic drugs that are commonly used to treat cancers as well as bacterial and HIV infections.
-
They bind selectively to interfaces as macromolecular machines assemble and are set in motion. The bound drugs transiently arrest the targeted molecular machines and desynchronize their concerted functions.
-
To provide an operational (empirical) definition of interfacial inhibition, we present five archetypical examples of interfacial inhibitors: the camptothecins, etoposide, the quinolone antibiotics, the vinca alkaloids and the novel anti-HIV inhibitor raltegravir.
-
We discuss the common and diverging elements between interfacial and allosteric inhibitors, and demonstrate that interfacial inhibitors can also be classified as orthosteric and allosteric inhibitors.
-
Finally, we give a perspective and provide specific examples for the rationale and methods to discover novel interfacial inhibitors.
Abstract
Interfacial inhibitors belong to a broad class of natural products and synthetic drugs that are commonly used to treat cancers as well as bacterial and HIV infections. They bind selectively to interfaces as macromolecular machines assemble and are set in motion. The bound drugs transiently arrest the targeted molecular machines, which can initiate allosteric effects, or desynchronize macromolecular machines that normally function in concert. Here, we review five archetypical examples of interfacial inhibitors: the camptothecins, etoposide, the quinolone antibiotics, the vinca alkaloids and the novel anti-HIV inhibitor raltegravir. We discuss the common and diverging elements between interfacial and allosteric inhibitors and give a perspective for the rationale and methods used to discover novel interfacial inhibitors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
03 February 2012
In Table 1, the information listed in the 'Substrates' column for 'Etoposide and teniposide' and 'Mitoxantrone' is incorrect; 'TOP1–DNA complex' should be 'TOP2–DNA complex' in both instances. This has been corrected in the online version of the article.
References
Conti, C. et al. Replication fork velocities at adjacent replication origins are coordinately modified during DNA replication in human cells. Mol. Biol. Cell 18, 3059–3067 (2007).
Sugino, A., Peebles, C. L., Kreuzer, K. N. & Cozzarelli, N. R. Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proc. Natl Acad. Sci. USA 74, 4767–4771 (1977).
Gellert, M., Mizuuchi, K., O'Dea, M. H., Itoh, T. & Tomizawa, J. I. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc. Natl Acad. Sci. USA 74, 4772–4776 (1977).
Pommier, Y., Leo, E., Zhang, H. & Marchand, C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol. 17, 421–433 (2010).
Staker, B. L. et al. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl Acad. Sci. USA 99, 15387–15392 (2002).
Staker, B. L. et al. Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J. Med. Chem. 48, 2336–2345 (2005).
Marchand, C. et al. A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of topoisomerase I-DNA covalent complexes. Mol. Cancer Ther. 5, 287–295 (2006).
Pommier, Y. & Cherfils, J. Interfacial protein inhibition: a nature's paradigm for drug discovery. Trends Pharmacol. Sci. 28, 136–145 (2005).
Pommier, Y. & Marchand, C. Interfacial inhibitors of protein-nucleic acid interactions. Curr. Med. Chem. Anti-Canc. Agents 5, 421–429 (2005).
Laponogov, I. et al. Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases. Nature Struct. Mol. Biol. 16, 667–669 (2009).
Laponogov, I. et al. Structural basis of gate-DNA breakage and resealing by type II topoisomerases. PLoS ONE 5, 8 (2010).
Bax, B. D. et al. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466, 935–940 (2010).
Hare, S. et al. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc. Natl Acad. Sci. USA 107, 20057–20062 (2010).
Krishnan, L. et al. Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc. Natl Acad. Sci. USA 107, 15910–15915 (2010).
Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010).
Wu, C. C. et al. Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science 333, 459–462 (2011).
Forterre, P. in DNA Topoisomerases and Cancer (ed. Pommier, Y.) 1–52 (Springer, New York, 2012).
Chrencik, J. E. et al. Mechanisms of camptothecin resistance by human topoisomerase I mutations. J. Mol. Biol. 339, 773–784 (2004).
Koster, D. A., Palle, K., Bot, E. S. M., Bjornsti, M. A. & Dekker, N. H. Antitumour drugs impede DNA uncoiling by topoisomerase I. Nature 448, 213–217 (2007).
Pommier, Y., Pourquier, P., Urasaki, Y., Wu, J. & Laco, G. Topoisomerase I inhibitors: selectivity and cellular resistance. Drug Resist. Updat. 2, 307–318 (1999).
Jaxel, C., Kohn, K. W., Wani, M. C., Wall, M. E. & Pommier, Y. Structure–activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res. 49, 1465–1469 (1989).
Eng, W. K., Faucette, L., Johnson, R. K. & Sternglanz, R. Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol. Pharmacol. 34, 755–760 (1988).
Nitiss, J. & Wang, J. C. DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc. Natl Acad. Sci. USA 85, 7501–7505 (1988).
Sirikantaramas, S., Yamazaki, M. & Saito, K. Mutations in topoisomerase I as a self-resistance mechanism coevolved with the production of the anticancer alkaloid camptothecin in plants. Proc. Natl Acad. Sci. USA 105, 6782–6786 (2008).
Fujimori, A., Harker, W. G., Kohlhagen, G., Hoki, Y. & Pommier, Y. Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell resistant to camptothecin. Cancer Res. 55, 1339–1346 (1995).
Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond. Nature Rev. Cancer 6, 789–802 (2006).
Pommier, Y. et al. Repair of topoisomerase I-mediated DNA damage. Prog. Nucleic Acid Res. Mol. Biol. 81, 179–229 (2006).
Capranico, G., Kohn, K. W. & Pommier, Y. Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin. Nucleic Acids Res. 18, 6611–6619 (1990).
Pommier, Y., Capranico, G., Orr, A. & Kohn, K. W. Local base sequence preferences for DNA cleavage by mammalian topoisomerase II in the presence of amsacrine or teniposide. Nucleic Acids Res. 19, 5973–5980 (1991).
Chen, G. L. et al. Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J. Biol. Chem. 259, 13560–13566 (1984).
Tewey, K. M., Chen, G. L., Nelson, E. M. & Liu, L. F. Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J. Biol. Chem. 259, 9182–9187 (1984).
Pommier, Y., Capranico, G., Orr, A. & Kohn, K. W. Distribution of topoisomerase II cleavage sites in SV40 DNA and the effects of drugs. J. Mol. Biol. 222, 909–924 (1991).
Capranico, G., Zunino, F., Kohn, K. W. & Pommier, Y. Sequence-selective topoisomerase II inhibition by anthracycline derivatives in SV40 DNA: relationship with DNA binding affinity and cytotoxicity. Biochemistry 29, 562–569 (1990).
Capranico, G., De Isabella, P., Tinelli, S., Bigioni, S. & Zunino, F. Similar sequence specificity of mitoxantrone and VM-26 stimulation of in vitro DNA cleavage by mammalian DNA topoisomerase II. Biochemistry 32, 3032–3048 (1993).
Heddle, J. G., Barnard, F. M., Wentzell, L. M. & Maxwell, A. The interaction of drugs with DNA gyrase: a model for the molecular basis of quinolone action. Nucleosides Nucleotides Nucleic Acids 19, 1249–1264 (2000).
De Jonge, N. et al. Rejuvenation of CcdB-poisoned gyrase by an intrinsically disordered protein domain. Mol. Cell 35, 154–163 (2009).
Williams, J. J. & Hergenrother, P. J. Exposing plasmids as the Achilles' heel of drug-resistant bacteria. Curr. Opin. Chem. Biol. 12, 389–399 (2008).
Dao-Thi, M. H. et al. Molecular basis of gyrase poisoning by the addiction toxin CcdB. J. Mol. Biol. 348, 1091–1102 (2005).
Ishida, R. et al. Inhibition of DNA topoisomerase II by ICRF-193 induces polyploidization by uncoupling chromosome dynamics from other cell cycle events. J. Cell Biol. 126, 1341–1351 (1994).
Andoh, T. & Ishida, R. Catalytic inhibitors of DNA topoisomerase II. Biochim. Biophys. Acta 1400, 155–171 (1998).
Classen, S., Olland, S. & Berger, J. M. Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. Proc. Natl Acad. Sci. USA 100, 10629–10634 (2003).
Dumontet, C. & Jordan, M. A. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nature Rev. Drug Discov. 9, 790–803 (2010).
Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nature Rev. Cancer 4, 253–265 (2004).
Gigant, B. et al. Structural basis for the regulation of tubulin by vinblastine. Nature 435, 519–522 (2005).
Hare, S. et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol. Pharmacol. 80, 565–572 (2011).
Marchand, C., Maddali, K., Metifiot, M. & Pommier, Y. HIV-1 IN inhibitors: 2010 update and perspectives. Curr. Top. Med. Chem. 9, 1016–1037 (2009).
Metifiot, M., Marchand, C., Maddali, K. & Pommier, Y. Resistance to integrase inhibitors. Viruses 2, 1347–1366 (2010).
Metifiot, M. et al. Elvitegravir overcomes resistance to raltegravir induced by integrase mutation Y143. AIDS 25, 1175–1178 (2011).
Pommier, Y., Johnson, A. & Marchand, C. Integrase inhibitors to treat HIV/AIDS. Nature Rev. Drug Discov. 4, 236–248 (2005).
Li, X., Krishnan, L., Cherepanov, P. & Engelman, A. Structural biology of retroviral DNA integration. Virology 411, 194–205 (2011).
Zhao, X. Z. et al. Development of tricyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett. 21, 2986–2990 (2011).
Wells, J. A. & McClendon, C. L. Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450, 1001–1009 (2007).
Changeux, J. P. & Taly, A. Nicotinic receptors, allosteric proteins and medicine. Trends Mol. Med. 14, 93–102 (2008).
Burgin, A. B. et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nature Biotech. 28, 63–70 (2010).
Changeux, J.-P. 50th anniversary of the word “allosteric”. Protein Science 20, 1119–1124 (2011).
Monod, J., Changeux, J. P. & Jacob, F. Allosteric proteins and cellular control systems. J. Mol. Biol. 6, 306–329 (1963).
Pommier, Y. et al. DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the carribean tunicate Ecteinascidia Turbinata. Biochemistry 35, 13303–13309 (1996).
Koshland, D. E. Jr, Nemethy, G. & Filmer, D. Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry 5, 365–385 (1966).
Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010).
Brueckner, F. & Cramer, P. Structural basis of transcription inhibition by α-amanitin and implications for RNA polymerase II translocation. Nature Struct. Mol. Biol. 15, 811–818 (2008).
Bushnell, D. A., Cramer, P. & Kornberg, R. D. Structural basis of transcription: α-amanitin–RNA polymerase II cocrystal at 2.8 Å resolution. Proc. Natl Acad. Sci. USA 99, 1218–1222 (2002).
Hibbs, R. E. et al. Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal α7 nicotinic acetylcholine receptor. EMBO J. 28, 3040–3051 (2009).
Nury, H. et al. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469, 428–431 (2011).
Sigel, E. & Luscher, B. P. A closer look at the high affinity benzodiazepine binding site on GABAA receptors. Curr. Top. Med. Chem. 11, 241–246 (2011).
Renault, L., Guibert, B. & Cherfils, J. Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor. Nature 426, 525–530 (2003).
Mossessova, E., Corpina, R. A. & Goldberg, J. Crystal structure of ARF1• Sec7 complexed with Brefeldin A and its implications for the guanine nucleotide exchange mechanism. Mol. Cell 12, 1403–1411 (2003).
Ravelli, R. B. G. et al. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature 428, 198–202 (2004).
Jin, L. & Harrison, S. C. Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin. Proc. Natl Acad. Sci. USA 99, 13522–13526 (2002).
Huai, Q. et al. Crystal structure of calcineurin–cyclophilin–cyclosporin shows common but distinct recognition of immunophilin–drug complexes. Proc. Natl Acad. Sci. USA 99, 12037–12042 (2002).
Roca, J., Ishida, R., Berger, J. M., Andoh, T. & Wang, J. C. Antitumor bisdioxopiperazines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp. Proc. Natl Acad. Sci. USA 91, 1781–1785 (1994).
Takebayashi, Y. et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nature Med. 7, 961–966 (2001).
Nettles, J. H. et al. The binding mode of epothilone A on α,β-tubulin by electron crystallography. Science 305, 866–869 (2004).
Kissinger, C. R. et al. Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex. Nature 378, 641–644 (1995).
Griffith, J. P. et al. X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell 82, 507–522 (1995).
Tesmer, J. J., Sunahara, R. K., Gilman, A. G. & Sprang, S. R. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsα•GTPγS. Science 278, 1907–1916 (1997).
Wurtele, M., Jelich-Ottmann, C., Wittinghofer, A. & Oecking, C. Structural view of a fungal toxin acting on a 14-3-3 regulatory complex. EMBO J. 22, 987–994 (2003).
Agrawal, R. K. & Frank, J. Structural studies of the translational apparatus. Curr. Opin. Struct. Biol. 9, 215–221 (1999).
Laurberg, M. et al. Structure of a mutant EF-G reveals domain III and possibly the fusidic acid binding site. J. Mol. Biol. 303, 593–603 (2000).
Ioanoviciu, A. et al. Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA–enzyme–inhibitor complex as determined by X-ray crystallographic analysis. J. Med. Chem. 48, 4803–4814 (2005).
Choi, J., Chen, J., Schreiber, S. L. & Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239–242 (1996).
Moellering, R. E. et al. Direct inhibition of the NOTCH transcription factor complex. Nature 462, 182–188 (2009).
Edwards, M. J. et al. A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase. Science 326, 1415–1418 (2009).
Snyder, J. P., Nettles, J. H., Cornett, B., Downing, K. H. & Nogales, E. The binding conformation of taxol in β-tubulin: a model based on electron crystallographic density. Proc. Natl Acad. Sci. USA 98, 5312–5316 (2001).
Bowen, W. S., Van Dyke, N., Murgola, E. J., Lodmell, J. S. & Hill, W. E. Interaction of thiostrepton and elongation factor-G with the ribosomal protein L11-binding domain. J. Biol. Chem. 280, 2934–2943 (2004).
Acknowledgements
Our studies are supported by the Center for Cancer Research, the Intramural Program of the National Cancer Institute, US National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Rights and permissions
About this article
Cite this article
Pommier, Y., Marchand, C. Interfacial inhibitors: targeting macromolecular complexes. Nat Rev Drug Discov 11, 25–36 (2012). https://doi.org/10.1038/nrd3404
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrd3404
This article is cited by
-
Replication-associated formation and repair of human topoisomerase IIIα cleavage complexes
Nature Communications (2023)
-
DNA–protein cross-link repair: what do we know now?
Cell & Bioscience (2020)
-
Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study
BMC Cancer (2019)
-
Novel tetrahydroacridine derivatives with iodobenzoic moieties induce G0/G1 cell cycle arrest and apoptosis in A549 non-small lung cancer and HT-29 colorectal cancer cells
Molecular and Cellular Biochemistry (2019)
-
A rapid high-resolution method for resolving DNA topoisomers
BMC Research Notes (2018)