3 Conclusion
There is growing interest in the development of compounds able to
modulate PPIs, as they control a large number of physiological
events and are involved in many diseases [54, 55]. However, PPIs
are considered challenging targets for the development of chemical
probes or drugs. PDZ domains belong to PPI networks, and therefore are essentially considered poor druggable targets. This is confirmed by the screening of large compound libraries in which no
high affinity hits were yet identified [20]. Despite this classification
as being poor druggable targets, dozens of studies have reported
small organic compounds able to disrupt PPIs between PDZ
domains and their endogenous protein partners. Various strategies
involving a combination of experimental screening, biophysical
methods, molecular modeling, and organic chemistry were
employed to tackle the development of PDZ inhibitors. However,
most nonpeptide compounds reported thus far exhibited moderate
affinity in the 10 μM range. Promisingly, several integrative studies
recently reported submicromolar compounds, enabling future
opportunities for the use of PDZ inhibitors as important tools to
decipher biological processes and as potential therapeutics to treat
some cancers and neurological diseases.
References
1. Wang NX, Lee HJ, Zheng JJ (2008) Therapeutic use of PDZ protein-protein interaction
antagonism. Drug News Perspect 21
(3):137–141
2. Chi CN, Bach A, Strømgaard K, Gianni S,
Jemth P (2012) Ligand binding by PDZ
domains. Biofactors 38(5):338–348. https://
doi.org/10.1002/biof.1031
3. Dev KK (2004) Making protein interactions
druggable: targeting PDZ domains. Nat Rev
Drug Discov 3(12):1047–1056. https://doi.
org/10.1038/nrd1578
4. Grillo-Bosch D, Choquet D, Sainlos M (2013)
Inhibition of PDZ domain-mediated interactions. Drug Discov Today Technol 10(4):
e531–e540.
https://doi.org/10.1016/j.
ddtec.2012.10.003
5. Songyang Z, Fanning AS, Fu C, Xu J, Marfatia
SM, Chishti AH, Crompton A, Chan AC,
Anderson JM, Cantley LC (1997) Recognition
of unique carboxyl-terminal motifs by distinct
PDZ domains. Science 275(5296):73–77.
https://doi.org/10.1126/science.275.
5296.73
6. Wiedemann U, Boisguerin P, Leben R,
Leitner D, Krause G, Moelling K, VolkmerEngert R, Oschkinat H (2004) Quantification
of PDZ domain specificity, prediction of ligand
affinity and rational design of super-binding
peptides. J Mol Biol 343(3):703–718.
https://doi.org/10.1016/j.jmb.2004.08.064
7. Wawrzyniak
AM,
Vermeiren
E,
Zimmermann P, Ivarsson Y (2012) Extensions
of PSD-95/discs large/ZO-1 (PDZ) domains
influence lipid binding and membrane targeting of syntenin-1. FEBS Lett 586
(10):1445–1451. https://doi.org/10.1016/j.
febslet.2012.04.024
8. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M,
Gurd JW, Wang YT, Salter MW, Tymianski M
(2002) Treatment of ischemic brain damage by
perturbing NMDA receptor- PSD-95 protein
interactions. Science 298(5594):846–850.
https://doi.org/10.1126/science.1072873
9. Thorsen TS, Madsen KL, Rebola N, Rathje M,
Anggono V, Bach A, Moreira IS, StuhrHansen N, Dyhring T, Peters D, Beuming T,
Huganir R, Weinstein H, Mulle C,
Strømgaard K, Rønn LC, Gether U (2010)
Identification of a small-molecule inhibitor of
the PICK1 PDZ domain that inhibits hippocampal LTP and LTD. Proc Natl Acad Sci U S
286
Laurent Hoffer et al.
There is growing interest in the development of compounds able to
modulate PPIs, as they control a large number of physiological
events and are involved in many diseases [54, 55]. However, PPIs
are considered challenging targets for the development of chemical
probes or drugs. PDZ domains belong to PPI networks, and therefore are essentially considered poor druggable targets. This is confirmed by the screening of large compound libraries in which no
high affinity hits were yet identified [20]. Despite this classification
as being poor druggable targets, dozens of studies have reported
small organic compounds able to disrupt PPIs between PDZ
domains and their endogenous protein partners. Various strategies
involving a combination of experimental screening, biophysical
methods, molecular modeling, and organic chemistry were
employed to tackle the development of PDZ inhibitors. However,
most nonpeptide compounds reported thus far exhibited moderate
affinity in the 10 μM range. Promisingly, several integrative studies
recently reported submicromolar compounds, enabling future
opportunities for the use of PDZ inhibitors as important tools to
decipher biological processes and as potential therapeutics to treat
some cancers and neurological diseases.
References
1. Wang NX, Lee HJ, Zheng JJ (2008) Therapeutic use of PDZ protein-protein interaction
antagonism. Drug News Perspect 21
(3):137–141
2. Chi CN, Bach A, Strømgaard K, Gianni S,
Jemth P (2012) Ligand binding by PDZ
domains. Biofactors 38(5):338–348. https://
doi.org/10.1002/biof.1031
3. Dev KK (2004) Making protein interactions
druggable: targeting PDZ domains. Nat Rev
Drug Discov 3(12):1047–1056. https://doi.
org/10.1038/nrd1578
4. Grillo-Bosch D, Choquet D, Sainlos M (2013)
Inhibition of PDZ domain-mediated interactions. Drug Discov Today Technol 10(4):
e531–e540.
https://doi.org/10.1016/j.
ddtec.2012.10.003
5. Songyang Z, Fanning AS, Fu C, Xu J, Marfatia
SM, Chishti AH, Crompton A, Chan AC,
Anderson JM, Cantley LC (1997) Recognition
of unique carboxyl-terminal motifs by distinct
PDZ domains. Science 275(5296):73–77.
https://doi.org/10.1126/science.275.
5296.73
6. Wiedemann U, Boisguerin P, Leben R,
Leitner D, Krause G, Moelling K, VolkmerEngert R, Oschkinat H (2004) Quantification
of PDZ domain specificity, prediction of ligand
affinity and rational design of super-binding
peptides. J Mol Biol 343(3):703–718.
https://doi.org/10.1016/j.jmb.2004.08.064
7. Wawrzyniak
AM,
Vermeiren
E,
Zimmermann P, Ivarsson Y (2012) Extensions
of PSD-95/discs large/ZO-1 (PDZ) domains
influence lipid binding and membrane targeting of syntenin-1. FEBS Lett 586
(10):1445–1451. https://doi.org/10.1016/j.
febslet.2012.04.024
8. Aarts M, Liu Y, Liu L, Besshoh S, Arundine M,
Gurd JW, Wang YT, Salter MW, Tymianski M
(2002) Treatment of ischemic brain damage by
perturbing NMDA receptor- PSD-95 protein
interactions. Science 298(5594):846–850.
https://doi.org/10.1126/science.1072873
9. Thorsen TS, Madsen KL, Rebola N, Rathje M,
Anggono V, Bach A, Moreira IS, StuhrHansen N, Dyhring T, Peters D, Beuming T,
Huganir R, Weinstein H, Mulle C,
Strømgaard K, Rønn LC, Gether U (2010)
Identification of a small-molecule inhibitor of
the PICK1 PDZ domain that inhibits hippocampal LTP and LTD. Proc Natl Acad Sci U S
286
Laurent Hoffer et al.