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phosphodiesterase 12

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 3207

Nomenclature: phosphodiesterase 12

Family: Phosphodiesterases (other)

Contents:

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 Q6L8Q7 (Hs), Q3TIU4 (Mm), Q6AXQ5 (Rn)
BRENDA 3.1.13.4
ChEMBL Target CHEMBL4523342 (Hs)
Ensembl Gene ENSG00000174840 (Hs), ENSMUSG00000043702 (Mm), ENSRNOG00000059442 (Rn)
Entrez Gene 201626 (Hs), 211948 (Mm), 306231 (Rn)
Human Protein Atlas ENSG00000174840 (Hs)
KEGG Enzyme 3.1.13.4
KEGG Gene hsa:201626 (Hs), mmu:211948 (Mm), rno:306231 (Rn)
OMIM 616519 (Hs)
Pharos Q6L8Q7 (Hs)
RefSeq Nucleotide NM_177966 (Hs), NM_178668 (Mm), NM_001411708 (Rn)
RefSeq Protein NP_808881 (Hs), NP_848783 (Mm), NP_001398637 (Rn)
UniProtKB Q6L8Q7 (Hs), Q3TIU4 (Mm), Q6AXQ5 (Rn)
Wikipedia PDE12 (Hs)
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

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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 has potential as a pan-RNA virus antiviral drug target. Selective 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 (CO-63 and CO-17; structures not disclosed) have demonstrated antiviral activity against a range of RNA viruses, including hepatitis C virus, dengue virus, West Nile virus and SARS-CoV-2 [3]

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

References

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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 et al.. (2023) Inhibition of phosphodiesterase 12 results in antiviral activity against several RNA viruses including SARS-CoV-2. J Gen Virol, 104 (7). [PMID:37432877]

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 31/07/2023. Accessed on 26/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=3207.