Top ▲

phosphodiesterase 12

Click here for help

Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 3207

Nomenclature: phosphodiesterase 12

Family: Phosphodiesterases (other)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 609 3p14.3 PDE12 phosphodiesterase 12
Mouse - 608 14 A3 Pde12 phosphodiesterase 12
Rat - 608 16p16 Pde12 phosphodiesterase 12
Database Links Click here for help
Alphafold
BRENDA
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  The structure of human PDE12 residues 161-609 in complex with GSK3036342A (compound 3)
PDB Id:  4Z2B
Ligand:  compound 3 [PMID: 26055709]
Resolution:  1.8Å
Species:  Human
References:  4
Enzyme Reaction Click here for help
EC Number: 3.1.13.4

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 3 [PMID: 26055709] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.8 pKi 4
pKi 7.8 (Ki 1.75x10-8 M) [4]
compound 1 [PMID: 26055709] Small molecule or natural product Hs Inhibition 9.1 pIC50 4
pIC50 9.1 (IC50 7.94x10-10 M) [4]
compound 3 [PMID: 26055709] Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.7 pIC50 4
pIC50 7.7 (IC50 2.09x10-8 M) [4]
Immunopharmacology Comments
PDE12 acts as a negative regulator of a 2-5A (2′,5′-linked oligoadenylate) activated pathway of the innate interferon response to viral infection. Some RNA viruses, including coronaviruses, encode 2',5'-phosphodiesterases as a mechanism to combat their hosts' antiviral immunity [5-6]. Inhibitors of PDE12 function are proposed as novel antiviral agents [3-4].
General Comments
RNase L which is part of the 2',5'-oligoadenylate synthetase (OAS)-Ribonuclease L (RNase L) innate immune pathway, is activated by 2',5'-oligoadenylates (2-5As; a signalling intermediate of OAS activity), with active RNase L going on to hydrolyse viral (and cellular) RNAs and suppress viral replication [1-2,4]. Phosphodiesterase 12 (PDE12) is a 2-5A degrading enzyme that counteracts RNase L activation during viral infections, to provide a braking mechanism on the innate interferon-mediated antiviral response [7]. PDE12 inhibitors are proposed as a method to maintain the presence of 2-5As and activation of RNaseL, to induce a clinically useful antiviral effect [3-4]. Two PDE12-selective inhibitors that were delevoped by Riotech Pharmaceuticals (compounds 63 and 17) have demonstrated antiviral activity against a range of RNA viruses, including SARS-CoV-2 [3] (bioRxiv preprint, Sept 2022). The chemical structures of these lead compounds were not disclosed in the preprint.

Some RNA viruses, including coronaviruses, encode 2',5'-phosphodiesterases as an inbuilt capability to combat their hosts' antiviral immune response [4-6].

References

Show »

1. Dong B, Silverman RH. (1995) 2-5A-dependent RNase molecules dimerize during activation by 2-5A. J Biol Chem, 270 (8): 4133-7. [PMID:7876164]

2. Huang H, Zeqiraj E, Dong B, Jha BK, Duffy NM, Orlicky S, Thevakumaran N, Talukdar M, Pillon MC, Ceccarelli DF et al.. (2014) Dimeric structure of pseudokinase RNase L bound to 2-5A reveals a basis for interferon-induced antiviral activity. Mol Cell, 53 (2): 221-34. [PMID:24462203]

3. Thursz M, Sadiq F, Tree JA, Karayiannis P, Beasley DWC, Dejnirattisai W, Mongkolsapaya J, Screaton G, Wand M, Elmore MJ. (2022) Inhibition of Phosphodiesterase 12 results in Antiviral Activity against several RNA Viruses including SARS-CoV-2. bioRxiv, Preprint. DOI: 10.1101/2022.09.23.509178

4. Wood ER, Bledsoe R, Chai J, Daka P, Deng H, Ding Y, Harris-Gurley S, Kryn LH, Nartey E, Nichols J et al.. (2015) The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors. J Biol Chem, 290 (32): 19681-96. [PMID:26055709]

5. Zhang R, Jha BK, Ogden KM, Dong B, Zhao L, Elliott R, Patton JT, Silverman RH, Weiss SR. (2013) Homologous 2',5'-phosphodiesterases from disparate RNA viruses antagonize antiviral innate immunity. Proc Natl Acad Sci U S A, 110 (32): 13114-9. [PMID:23878220]

6. Zhao L, Jha BK, Wu A, Elliott R, Ziebuhr J, Gorbalenya AE, Silverman RH, Weiss SR. (2012) Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology. Cell Host Microbe, 11 (6): 607-16. [PMID:22704621]

7. Zhou A, Hassel BA, Silverman RH. (1993) Expression cloning of 2-5A-dependent RNAase: a uniquely regulated mediator of interferon action. Cell, 72 (5): 753-65. [PMID:7680958]

How to cite this page

Phosphodiesterases (other): phosphodiesterase 12. Last modified on 11/10/2022. Accessed on 04/12/2022. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3207.