Antibody-enabled small-molecule drug discovery

Although antibody-based therapeutics have become firmly established as medicines for serious diseases, the value of antibodies as tools in the early stages of small-molecule drug discovery is only beginning to be realized. In particular, antibodies may provide information to reduce risk in small-molecule drug discovery by enabling the validation of targets and by providing insights into the design of small-molecule screening assays. Moreover, antibodies can act as guides in the quest for small molecules that have the ability to modulate protein–protein interactions, which have traditionally only been considered to be tractable targets for biological drugs. The development of small molecules that have similar therapeutic effects to current biologics has the potential to benefit a broader range of patients at earlier stages of disease.

[1]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[2]  Rob Leurs,et al.  Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis. , 2011, Journal of the American Chemical Society.

[3]  Colin L Masters,et al.  Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease , 2011, The Journal of Neuroscience.

[4]  C. Wstermeire Structure at 2.7 A resolution of the Paracococcus dendrificans two-subunit cytochrome c oxidase coupled with an antibody Fv fragment , 1997 .

[5]  S. Sidhu,et al.  Two-state selection of conformation-specific antibodies , 2009, Proceedings of the National Academy of Sciences.

[6]  A. Christopoulos Allosteric binding sites on cell-surface receptors: novel targets for drug discovery , 2002, Nature Reviews Drug Discovery.

[7]  W. Delano Unraveling hot spots in binding interfaces: progress and challenges. , 2002, Current opinion in structural biology.

[8]  W. Hol,et al.  Structures of a key interaction protein from the Trypanosoma brucei editosome in complex with single domain antibodies. , 2010, Journal of structural biology.

[9]  T. Tuschl,et al.  Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells , 2001, Nature.

[10]  A. Cattaneo,et al.  In vivo selection of intrabodies specifically targeting protein-protein interactions: a general platform for an "undruggable" class of disease targets. , 2008, Journal of biotechnology.

[11]  Jonathan Goldberg,et al.  Crystal structure of ARF1*Sec7 complexed with Brefeldin A and its implications for the guanine nucleotide exchange mechanism. , 2003, Molecular cell.

[12]  Marko Hyvönen,et al.  Targeting protein-protein interactions and fragment-based drug discovery. , 2012, Topics in current chemistry.

[13]  P. Hajduk,et al.  NMR-based screening in drug discovery , 1999, Quarterly Reviews of Biophysics.

[14]  R. Webster,et al.  Recombinant anti-sialidase single-chain variable fragment antibody. Characterization, formation of dimer and higher-molecular-mass multimers and the solution of the crystal structure of the single-chain variable fragment/sialidase complex. , 1994, European journal of biochemistry.

[15]  Holger Gohlke,et al.  Targeting protein-protein interactions with small molecules: challenges and perspectives for computational binding epitope detection and ligand finding. , 2006, Current medicinal chemistry.

[16]  Lode Wyns,et al.  Crystal Structure of the Intrinsically Flexible Addiction Antidote MazE* , 2003, Journal of Biological Chemistry.

[17]  C. Sachse,et al.  Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils , 2007, Proceedings of the National Academy of Sciences.

[18]  Hartmut Michel,et al.  Structure at 2.8 Å resolution of cytochrome c oxidase from Paracoccus denitrificans , 1995, Nature.

[19]  C. Duyckaerts,et al.  Single-domain antibodies recognize selectively small oligomeric forms of amyloid beta, prevent Abeta-induced neurotoxicity and inhibit fibril formation. , 2009, Molecular immunology.

[20]  Christopher M. Dobson,et al.  A camelid antibody fragment inhibits the formation of amyloid fibrils by human lysozyme , 2003, Nature.

[21]  S. Iwata,et al.  G protein-coupled receptor inactivation by an allosteric inverse-agonist antibody , 2011, Nature.

[22]  D. Kirchhofer,et al.  Structural and mechanistic insight into how antibodies inhibit serine proteases. , 2010, The Biochemical journal.

[23]  A. Koide,et al.  Toward chaperone‐assisted crystallography: Protein engineering enhancement of crystal packing and X‐ray phasing capabilities of a camelid single‐domain antibody (VHH) scaffold , 2008, Protein science : a publication of the Protein Society.

[24]  J. Boonstra,et al.  The development of activating and inhibiting camelid VHH domains against human protein kinase C epsilon. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[25]  C. Dobson,et al.  Structure and properties of a complex of α-synuclein and a single-domain camelid antibody. , 2010, Journal of molecular biology.

[26]  Philip J. Hajduk,et al.  Fragment-based lead discovery: challenges and opportunities , 2011, J. Comput. Aided Mol. Des..

[27]  J. Weissenbach,et al.  Mutations in PCSK9 cause autosomal dominant hypercholesterolemia , 2003, Nature Genetics.

[28]  T. Rabbitts,et al.  Intracellular antibodies and challenges facing their use as therapeutic agents. , 2003, Trends in molecular medicine.

[29]  Annik Prat,et al.  The biology and therapeutic targeting of the proprotein convertases , 2012, Nature Reviews Drug Discovery.

[30]  J. Changeux,et al.  Allosteric proteins and cellular control systems. , 1963, Journal of molecular biology.

[31]  L. Wyns,et al.  Atomic structure of a nanobody-trapped domain-swapped dimer of an amyloidogenic β2-microglobulin variant , 2011, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. Wallace Novel targets for drug discovery , 1996 .

[33]  H. Michel,et al.  Structure at 2.7 A resolution of the Paracoccus denitrificans two-subunit cytochrome c oxidase complexed with an antibody FV fragment. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Walter Huber,et al.  Fragment-Based Screening Using Surface Plasmon Resonance Technology , 2009, Journal of biomolecular screening.

[35]  R. Stevens,et al.  A single-domain llama antibody potently inhibits the enzymatic activity of botulinum neurotoxin by binding to the non-catalytic alpha-exosite binding region. , 2010, Journal of molecular biology.

[36]  J. Steyaert,et al.  Constraining enzyme conformational change by an antibody leads to hyperbolic inhibition. , 2011, Journal of molecular biology.

[37]  J. Steyaert,et al.  Substrate-dependent modulation of enzyme activity by allosteric effector antibodies. , 2009, Biochimica et biophysica acta.

[38]  G. Air,et al.  Distribution of sequence differences in influenza N9 neuraminidase of tern and whale viruses and crystallization of the whale neuraminidase complexed with antibodies. , 1987, Virology.

[39]  Matthew P Jacobson,et al.  Turning a protein kinase on or off from a single allosteric site via disulfide trapping , 2011, Proceedings of the National Academy of Sciences.

[40]  A. Kossiakoff,et al.  Allosteric Control of Ligand Binding Affinity Using Engineered Conformation-Specific Effector Proteins , 2010, Nature Structural &Molecular Biology.

[41]  Anthony M Giannetti,et al.  From experimental design to validated hits a comprehensive walk-through of fragment lead identification using surface plasmon resonance. , 2011, Methods in enzymology.

[42]  D. Bartel,et al.  A portable RNA sequence whose recognition by a synthetic antibody facilitates structural determination , 2010, Nature Structural &Molecular Biology.

[43]  S. Rasmussen,et al.  Structure of a nanobody-stabilized active state of the β2 adrenoceptor , 2010, Nature.

[44]  R. Nussinov,et al.  Is allostery an intrinsic property of all dynamic proteins? , 2004, Proteins.

[45]  Peter M Fischer,et al.  Small-molecule inhibitors of MDM2 as new anticancer therapeutics. , 2010, Seminars in cancer biology.

[46]  T. Blundell,et al.  Structural biology in fragment-based drug design. , 2010, Current opinion in structural biology.

[47]  Jan Steyaert,et al.  Crystal structure of the N-terminal domain of the secretin GspD from ETEC determined with the assistance of a nanobody. , 2009, Structure.

[48]  C. Rudin,et al.  Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  A. Lawson,et al.  High-Throughput Screening for High Affinity Antibodies , 2009 .

[50]  M Kahn,et al.  Design and synthesis of a mimetic from an antibody complementarity-determining region. , 1991, Science.

[51]  P. Hajduk,et al.  Discovering High-Affinity Ligands for Proteins: SAR by NMR , 1996, Science.

[52]  J. Maynard,et al.  Conversion of scFv peptide-binding specificity for crystal chaperone development. , 2011, Protein engineering, design & selection : PEDS.

[53]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[54]  Razvan C. Bunescu,et al.  Consolidating the set of known human protein-protein interactions in preparation for large-scale mapping of the human interactome , 2005, Genome Biology.

[55]  James R Horn,et al.  Allosteric inhibition through core disruption. , 2004, Journal of molecular biology.

[56]  P. Hajduk,et al.  A decade of fragment-based drug design: strategic advances and lessons learned , 2007, Nature Reviews Drug Discovery.

[57]  W. Hol,et al.  Nanobody-aided structure determination of the EpsI:EpsJ pseudopilin heterodimer from Vibrio vulnificus. , 2009, Journal of structural biology.

[58]  R. MacKinnon,et al.  Chemistry of ion coordination and hydration revealed by a K+ channel–Fab complex at 2.0 Å resolution , 2001, Nature.

[59]  Sarah Crunkhorn Trial watch: PCSK9 antibody reduces LDL cholesterol , 2012, Nature Reviews Drug Discovery.

[60]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

[61]  H. Jhoti,et al.  Fragment-based drug discovery using rational design. , 2007, Ernst Schering Foundation symposium proceedings.

[62]  Magnus Björsne,et al.  Label-Free Primary Screening and Affinity Ranking of Fragment Libraries Using Parallel Analysis of Protein Panels , 2008, Journal of biomolecular screening.

[63]  J. Tait,et al.  Challenges and opportunities. , 1996, Journal of psychiatric and mental health nursing.

[64]  Jacqueline Cherfils,et al.  Structure-based discovery of an inhibitor of Arf activation by Sec7 domains through targeting of protein–protein complexes , 2007, Proceedings of the National Academy of Sciences.

[65]  M. Rossmann,et al.  Preparation and crystallization of a human immunodeficiency virus p24-Fab complex. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[66]  D. Barford,et al.  Conformation-Sensing Antibodies Stabilize the Oxidized Form of PTP1B and Inhibit Its Phosphatase Activity , 2011, Cell.

[67]  D. Kirchhofer,et al.  Unraveling the allosteric mechanism of serine protease inhibition by an antibody. , 2009, Structure.