5naw

From Proteopedia

Complement factor D in complex with the inhibitor (1R,3S,5R)-2-Aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-[(1-carbamoyl-1H-indol-3-yl)-amide] 3-[(3-trifluoromethoxy-phenyl)-amide]

PDB ID 5naw

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Structural highlights

5naw is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.25Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CFAD_HUMAN Defects in CFD are the cause of complement factor D deficiency (CFDD) [MIM:613912. CFDD is an immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway.

Function

CFAD_HUMAN Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway.

Publication Abstract from PubMed

The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.

Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.,Lorthiois E, Anderson K, Vulpetti A, Rogel O, Cumin F, Ostermann N, Steinbacher S, Mac Sweeney A, Delgado O, Liao SM, Randl S, Rudisser S, Dussauge S, Fettis K, Kieffer L, de Erkenez A, Yang L, Hartwieg C, Argikar UA, La Bonte LR, Newton R, Kansara V, Flohr S, Hommel U, Jaffee B, Maibaum J J Med Chem. 2017 Jul 13;60(13):5717-5735. doi: 10.1021/acs.jmedchem.7b00425. Epub, 2017 Jun 30. PMID:28621538^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lorthiois E, Anderson K, Vulpetti A, Rogel O, Cumin F, Ostermann N, Steinbacher S, Mac Sweeney A, Delgado O, Liao SM, Randl S, Rudisser S, Dussauge S, Fettis K, Kieffer L, de Erkenez A, Yang L, Hartwieg C, Argikar UA, La Bonte LR, Newton R, Kansara V, Flohr S, Hommel U, Jaffee B, Maibaum J. Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo. J Med Chem. 2017 Jul 13;60(13):5717-5735. doi: 10.1021/acs.jmedchem.7b00425. Epub, 2017 Jun 30. PMID:28621538 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b00425