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complement factor D

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2842

Nomenclature: complement factor D

Family: 3.4.21.46 Complement factor D

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 253 19p13.3 CFD complement factor D
Mouse - 259 10 39.72 cM Cfd complement factor D (adipsin)
Rat - 263 7q11 Cfd complement factor D
Gene and Protein Information Comments
Amino acid counts are for the preproproteins.
Previous and Unofficial Names Click here for help
complement factor D (adipsin)
Database Links Click here for help
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
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:  HUMAN COMPLEMENT FACTOR D IN A P21 CRYSTAL FORM
PDB Id:  1HFD
Resolution:  2.3Å
Species:  Human
References:  3

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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
example 373 [WO2012093101] Small molecule or natural product Primary target of this compound Hs Inhibition 9.0 pIC50 1-2
pIC50 9.0 (IC50 1x10-9 M) [1-2]
compound 2 [PMID: 28621538] Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.2 pIC50 4
pIC50 8.2 (IC50 6x10-9 M) [4]
Description: Measuring inhibition of recombinant human complement FD catalytic domain, using a thioesterolysis-based assay with Z-Lys-thiobenzylester as the substrate.
Inhibitor Comments
SARS-CoV-2 and COVID-19: Experimental evidence suggests that excessive complement activation may be a driving force behind the diffuse endothelial damage, microvascular/thrombotic/coagulation abnormalties and hyperinflammation in severe COVID-19. The SARS-CoV-2 spike protein is reported to directly activate the alternative complement pathway, by disrupting factor H function at the cell surface [6]. To examine the complement hypothesis, a small molecule factor D inhibitor has been tested in an in vitro model of SARS-CoV-2 infection [6]. The compound of interest is ACH-145951 (Achillion Pharmaceuticals, structure not disclosed), which acts upstream of anti-C5 agents such as eculizumab and ravulizumab, so prevents the accumulation of both C3c and C5b on cells. ACH-145951 was found to block the complement activation that was induced by SARS-CoV-2 spike proteins in the cellular model.
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
lampalizumab Peptide Primary target of this compound Hs Binding 10.7 pKi 5
pKi 10.7 (Ki 2x10-11 M) [5]
Immunopharmacology Comments
A protease component of the alternative complement pathway; responsible for cleaving complement factor B.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0006957 complement activation, alternative pathway TAS
GO:0043312 neutrophil degranulation TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes
GO:0006956 complement activation TAS
GO:0006957 complement activation, alternative pathway TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Complement factor D deficiency; CFDD
Synonyms: Factor D deficiency [OMIM: 613912]
Recurrent Neisseria infections due to factor D deficiency [Orphanet: ORPHA169467]
OMIM: 613912
Orphanet: ORPHA169467

References

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1. Abdel-Magid AF. (2012) Factor D Inhibitors for the Treatment of AMD: Patent Highlight. ACS Med Chem Lett, 3 (10): 781-2. [PMID:24900375]

2. Altmann E, Hommel U, Lorthiois ELJ, Maibaum JK, Ostermann N, Quancard J, Randl SA, Rogel O, Simic O, Vulpetti A. (2012) Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (AMD). Patent number: WO2012093101. Assignee: Novartis Ag. Priority date: 04/01/2011. Publication date: 12/07/2012.

3. Jing H, Babu YS, Moore D, Kilpatrick JM, Liu XY, Volanakis JE, Narayana SV. (1998) Structures of native and complexed complement factor D: implications of the atypical His57 conformation and self-inhibitory loop in the regulation of specific serine protease activity. J Mol Biol, 282 (5): 1061-81. [PMID:9753554]

4. Lorthiois E, Anderson K, Vulpetti A, Rogel O, Cumin F, Ostermann N, Steinbacher S, Mac Sweeney A, Delgado O, Liao SM et al.. (2017) Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo. J Med Chem, 60 (13): 5717-5735. [PMID:28621538]

5. Loyet KM, Good J, Davancaze T, Sturgeon L, Wang X, Yang J, Le KN, Wong M, Hass PE, Campagne Mv et al.. (2014) Complement inhibition in cynomolgus monkeys by anti-factor d antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration. J Pharmacol Exp Ther, 351 (3): 527-37. [PMID:25232192]

6. Yu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA. (2020) Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood, 136 (18): 2080-2089. [PMID:32877502]

How to cite this page

3.4.21.46 Complement factor D: complement factor D. Last modified on 14/10/2020. Accessed on 16/04/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2842.