Abstract:
:Complement plays a vital role in our innate immune defense against invasive microorganisms. Excessive complement activation or insufficient control of activation on host cells, however, is associated with several chronic disorders. Essential to the activation and amplification of the Alternative Pathway (AP) of complement, Complement Factor D (CFD) is a specific serine protease that cleaves its unique substrate, Complement Factor B (CFB) in complex with an activated form of complement component 3 (C3), to generate the AP C3 convertases C3(H2O)Bb and C3bBb. These convertases comprise a central component in eliciting effector responses following AP activation, and they also enable a powerful amplification loop for both the Classical Pathway (CP) and Lectin Pathway (LP) of complement. Because CFD is not required for the activation of either the CP or LP, selective CFD inhibition presents a favorable therapeutic approach to modulating complement activity that leaves intact the effector functions following CP and LP activation and thus poses a lower risk of bacterial infection than other complement-directed approaches. This review provides an update on inhibitors of CFD, which have evolved from irreversible small molecules that demonstrate poor selectivity to reversible small molecules and monoclonal antibodies that demonstrate exceptional selectivity and potency. The reversible small-molecule inhibitor danicopan.
journal_name
Curr Med Chemjournal_title
Current medicinal chemistryauthors
Wiles JA,Galvan MD,Podos SD,Geffner M,Huang Mdoi
10.2174/0929867326666191001130342subject
Has Abstractpub_date
2020-01-01 00:00:00pages
4165-4180issue
25eissn
0929-8673issn
1875-533Xpii
CMC-EPUB-101110journal_volume
27pub_type
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journal_title:Current medicinal chemistry
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abstract::Resistance to quinolones and fluoroquinolones has been increasingly reported among human and veterinary isolates during the last three decades related to their wide clinical use. Until recently, the mechanisms of resistance to quinolones in Enterobacteriaceae were believed to be only chromosome-encoded, i.e. related t...
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