A novel series of potent and selective small molecule inhibitors of the complement component C1s (original) (raw)
Related papers
Biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s
Bioorganic & Medicinal Chemistry Letters, 2008
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Bioorganic & Medicinal Chemistry Letters, 2012
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemiareperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
Recent developments in low molecular weight complement inhibitors
Molecular Immunology, 2009
As a key part of the innate immune system, complement plays an important role not only in defending invading pathogens but also in many other biological processes. Inappropriate or excessive activation of complement has been linked to many autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. A wide array of low molecular weight complement inhibitors has been developed to target various components of the complement cascade. Their efficacy has been demonstrated in numerous in vitro and in vivo experiments. Though none of these inhibitors has reached the market so far, some of them have entered clinical trials and displayed promising results. This review provides a brief overview of the currently developed low molecular weight complement inhibitors, including short peptides and synthetic small molecules, with an emphasis on those targeting components C1 and C3, and the anaphylatoxin receptors.
Structural aspects and design of low-molecular-mass complement inhibitors
Biochemical Society Transactions, 2002
We present a mini-review on the structure-based design of three promising complement inhibitors. Firstly, we review compstatin, a 13-residue cyclic peptide that binds to C3 and inhibits the cleavage of C3 to C3a and C3b. Secondly, we review a six-residue cyclic peptide that binds to C5aR and antagonizes the binding of C5a to its receptor C5aR. Finally, we review three small molecules that bind to Factor D and inhibit the enzymic action of Factor D, during which Factor D proteolytically cleaves Factor B in complex with C3 or C3b.
A small-molecule inhibitor of C5 complement protein
Nature Chemical Biology, 2019
The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein. The complement system is part of the innate immune system and consists of more than 30 proteins that circulate in blood. Complement is activated by one of three pathways, the classical, alternative and lectin pathways, to bring about a series of proteolytic cleavages to either enhance the immune response or form the membrane-attack complex (MAC). C5 convertase is the last enzyme in the pathway that cleaves C5, a large 190-kDa glycosylated protein composed of two disulfide-linked chains, to release the C5a anaphylatoxin and C5b. C5b assembles with four additional complement proteins (C6, C7, C8 and C9) to form the MAC, which is a transmembrane channel that induces cell lysis 1,2. Soliris (eculizumab) is the only approved antibody therapeutic that targets C5 to treat paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS) and generalized myasthenia gravis (gMG) 3. Compounds 1 and 2 (Table 1) were initially described by Zhang et al. 4 as complement inhibitors that block alternative or classical pathway-induced C9 deposition, but not deposition of C3 and C4. Given the target of these molecules had not been defined, we activated complement in serum with and without compound present and analyzed for the generation of complement breakdown products to find the node in the pathway modulated by these small molecules (Supplementary Table 1 and Supplementary Fig. 1a,b). These results indicated that the cascade was inhibited at the point of C5 cleavage, since neither the C5 breakdown products C5a or C5b nor any other component downstream of C5 could be detected. We assessed whether compounds 1 and 2 interact directly with complement proteins using size-exclusion chromatography coupled to mass spectrometric detection (SEC-MS) of compound concentration. We observed compound binding to full-length C5 complement protein, but not C5a, C3b or C8 (Supplementary Fig. 1c). Given that both 1 and 2 bound only to the full-length C5 protein, we further assessed this interaction using dynamic scanning fluorimetry (DSF) and observed that both compounds increase the melting temperature for C5 by about 1.7-1.8 °C (Fig. 1a). To measure the affinity of 1 for C5, a fixed compound concentration of 1 was titrated with an increasing concentration of C5 and compound binding affinity was quantified using SEC-MS to be 445 nM (Supplementary Fig. 1d). We further confirmed that 1 and 2 interact with C5 by showing they increase resistance to protease digestion with α-chymotrypsin (Fig. 1b). An analog 3 that had very poor
Further structure-activity-relationship studies on A/C/D-ring analogs of complement inhibitor K-76
Bioorganic & Medicinal Chemistry Letters, 1995
A series of new A/C/D-ring analogs (4a-f, 15) of fungal metabolite K-76 (la) have been synthesized and evaluated for human complement inhibitory potency. The in vitro assay results of human complement-mediated hemolysis of A/C/D-ring analogs indicate that the carboxylic acid functionality at C-6 is more important than C-7. The presence of aldehydic group and the terpenoid diol in these analogs contribute little towards human complement inhibition. The role of the phenolic hydroxyl is critical as benzofurans 4a and 4b exhibit human complement inhibition similar to the natural product.
Advances in Experimental Medicine and Biology, 2008
To obtain proteins with the complement-depleting activity of Cobra Venom Factor (CVF), but with less immunogenicity, we have prepared human C3/CVF hybrid proteins, in which the C-terminus of the !-chain of human C3 is exchanged with homologous regions of the C-terminus of the "-chain of CVF. We show that these hybrid 1496, is shown to be effective in reducing complement-mediated damage in two disease models in mice, collagen-induced arthritis and myocardial ischemia/reperfusion injury.
The Biochemical journal, 1982
Interactions between proenzymic or activated complement subcomponents of C1 and C1 Inh (C1 inhibitor) were analysed by sucrose-density-gradient ultracentrifugation and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The interaction of C1 Inh with dimeric C1r in the presence of EDTA resulted into two bimolecular complexes accounting for a disruption of C1r. The interaction of C1 Inh with the Ca2+-dependent C1r2-C1s2 complex (8.8 S) led to an 8.5 S inhibited C1r-C1s-C1 Inh complex (1:1:2), indicating a disruption of C1r2 and of C1s2 on C1 Inh binding. The 8.5 S inhibited complex was stable in the presence of EDTA; it was also formed from a mixture of C1r, C1s and C1 Inh in the presence of EDTA or from bimolecular complexes of C1r-C1 Inh and C1s-C1 Inh. C1r II, a modified C1r molecule, deprived of a Ca2+-binding site after autoproteolysis, did not lead to an inhibited tetrameric complex on incubation with C1s and C1 Inh. These findings suggest that, when C1 Inh binds to C1r...