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Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (2) : 132-140     DOI: 10.1007/s11515-016-1394-2
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Targeting secret handshakes of biological processes for novel drug development
Rini Jacob,Anbalagan Moorthy()
School of Bio-Sciences and Technology, VIT University, Vellore-632014, India
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Abstract

In multicellular organisms, several biological processes control the rise and fall of life. Different cell types communicate and co-operate in response to different stimulus through cell to cell signaling and regulate biologic processes in the cell/organism. Signaling in multicellular organism has to be made very secretly so that only the target cell responds to the signal. Of all the biomolecules, nature chose mainly proteins for secret delivery of information both inside and outside the cell. During cell signaling, proteins physically interact and shake hands for transfer of secret information by a phenomenon called as protein – protein interactions (PPIs). In both, extra and intracellular signaling processes PPIs play a crucial role. PPIs involved in cellular signaling are the primary cause for cell proliferation, differentiation, movement, metabolism, death and various other biological processes not mentioned here. These secret handshakes are very specific for specific functions. Any alterations/malfunctions in particular PPIs results in diseased condition. An overview of signaling pathways and importance of PPIs in cellular function and possibilities of targeting PPIs for novel drug development are discussed in this review.

Keywords cell signaling      protein-protein interactions      peptide inhibitors     
Corresponding Authors: Anbalagan Moorthy   
Just Accepted Date: 06 April 2016   Online First Date: 26 April 2016    Issue Date: 17 May 2016
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Rini Jacob,Anbalagan Moorthy. Targeting secret handshakes of biological processes for novel drug development[J]. Front. Biol., 2016, 11(2): 132-140.
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http://journal.hep.com.cn/fib/EN/10.1007/s11515-016-1394-2
http://journal.hep.com.cn/fib/EN/Y2016/V11/I2/132
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Fig.1  Different sites where protein-protein interactions can be targeted.
Inhibitor Interacting proteins Effect of the inhibitor Reference
Ligand-receptor mediated inhibition using small molecules Lovastatin, BIRT377 LFA-1/ICAM interaction Inflammatory diseases and graft rejection after transplantation Kallen et al., 1999
SB 247464 Granulocyte-colony stimulating factor stimulant Neutropenia Tian et al., 1998
Ro26-4550 Interaction of IL-2 to IL-2Rα Immuno modulation Tilley et al., 1997
SP4206 Interaction of IL-2 to IL-2Rα Immuno modulation Thanos et al., 2003
U0126 MEK1/2 interaction with ERK Antagonize AP1 transactivation Favata et al., 1998
Small molecules inhibitors of PPI involved in signaling cascade CEP-1347 Kinase activity of MLKs Inhibits JNK signalling Saporito et al., 2001
Gleevec ATP binding site of β amyloid peptide Amyloid plaque formation in Alzheimer’s Netzer et al., 2003
SM164-Smac mimetic XIAP-Caspase interaction Induction of apoptosis in cancer cells Lu et al., 2008
CCG-17444 Shroom3-rho kinase interaction Axon outgrowth- neural repair Dickson et al., 2015
M2I-I( MAD 2 Inhibitor 1) MAD 2/CDC20 interaction Mitotic spindle assembly Kastl et al., 2015
Small molecule inhibitor E3 ligase VHL and HIF1α interaction Chronic anemia Buckley et al., 2012
PPA250 Inhibit iNOS dimerization Tissue damage during inflammation Ohtsuka et al., 2002
HA 14-1 BAK BH3/BCL2 interaction Tumor cells apoptosis Wang et al., 2000
Ppi inhibitors preventing nuclear translocation SC236 Rel/p65 translocation Inflammation inducing gastric cancer Wong et al., 2003
PPI inhibitors in the nucleus BILD 1263 HSV-Ribonucleotide inhibitor Prevents replication of HSV-1 and HSV-2 preventing herpes virus infections Liuzzi et al., 1994
Bazidoxifene Selective estrogen receptor modulator Treatment of post menopausal problems Li et al., 2014
Tab.1  List of different inhibitors inhibiting various PPIs and its applications
Fig.2  Different methods to target protein-protein interactions.
Class Peptide Peptide Sequence Inhibition
Peptides inhibiting Receptor-protein interactions Pep2-8 TVFTSWEEYLDWV PCSK9 protein binding to LDL Receptor (Zhang et al., 2014)
Akt in (AKT inhibitor) AVTDHPDRLWAWEKF TCL1-Akt interaction AKT kinase activity (Hiromura et al.,2004)
Peptides inhibiting protein interactions involved during signalling cascade I-JIP (Inhibitor of JNK based on JIP-1) GPGTGSGDTYRPKRPTTLNLF JNK activity towards c-Jun, Elk and ATF-2 (Barr et al., 2002)
NBD pepteide (NEMO-binding domain peptide) FTALDWSWLQTE IKKβ- NEMO interaction , inhibiting NF-κB activity (May et al., 2000)
MEK1 peptide inhibitor GYGRKKRRQRRRGMPKKKPTPIQLNP ERK activation by MEK (Kelemen et al., 2001)
TLR2-BBP RQIKIWFQNRRMKWKKLHKRDFVPGKWIID LPS induced ERK activation-TLR signalling(Toshchakov et al., 2007)
MK2i(MK2 inhibitor) WLRRIKAWLRRIKALNRQLGVAA TGF-β1-induced HSP27 phosphorylation (Lopes et al., 2009)
TAT-MKK3b peptide YGRKKRRQRRRGKGKSKRKKDLRI Prevents p38 activation by LPS induced TNFα secretion (Fu et al., 2008)
Peptides inhibiting nuclear translocation of proteins TLR4-BBP RQIKIWFQNRRMKWKKLHYRDFIPGVAIAA LPS induced NFκB translocation and IL-1β mRNA expression (Toshchakov et al., 2007)
PT5 peptide QGQVVSNGKSTDEQS TAB/p38 α interaction decreasing myocardial I/R injury ( Wang et al., 2013)
Peptides inhibiting protein interactions in the nucleus DPMI-α TNWYANLEKLLR p53-MDM2 interaction (Liu et al., 2010)
Tab.2  Peptide inhibitors targeting PPIs at various levels and its applications
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