compstatin and Macular-Degeneration

Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic.

Topics: Alanine; Amino Acid Sequence; Amino Acid Substitution; Binding Sites; Clinical Trials as Topic; Complement C3; Complement Inactivator Proteins; Escherichia coli; Forecasting; Humans; Inhibitory Concentration 50; Macular Degeneration; Models, Biological; Models, Chemical; Models, Molecular; Molecular Sequence Data; Peptides, Cyclic; Protein Binding; Protein Conformation; Protein Structure, Secondary

Given the complex etiology of age-related macular degeneration (AMD), treatments are developed to target intermediate/late stages of the disease. Unfortunately, the design of therapies for early stages of the disease is limited by our understanding of the mechanisms involved in the formation of basal deposits and drusen, the first clinical signs of AMD. During the last decade, the identification of common and rare alleles in complement genes as risk AMD variants in addition to the presence of active complement components in basal deposits and drusen has provided compelling evidence that the complement system plays a key role in the pathobiology of AMD. However, the mechanisms for complement activation in AMD are unknown. Here we propose that the activation of the complement system is a consequence of alterations in the aged extracellular matrix (ECM) of the retinal pigment epithelium (RPE)/Bruch's membrane (BrM), which favors the anchoring of complement C3b generated by convertase-independent cleavage of C3 via tick-over and produces a chronic activation of the alternative complement pathway.

Topics: Animals; Bruch Membrane; Clinical Trials as Topic; Complement C3; Complement C3b; Complement Pathway, Alternative; Drug Design; Extracellular Matrix; Eye Diseases, Hereditary; Humans; Immunoglobulin Fab Fragments; Macular Degeneration; Mice; Models, Immunological; Molecular Targeted Therapy; Peptides, Cyclic; Retinal Drusen; Retinal Pigment Epithelium

To redesign a complement-inhibiting peptide with the potential to become a therapeutic for dry and wet age-related macular degeneration (AMD).. We present a new potent peptide (Peptide 2) of the compstatin family. The peptide is developed by rational design, based on a mechanistic binding hypothesis, and structural and physicochemical properties derived from molecular dynamics (MD) simulation. The inhibitory activity, efficacy, and solubility of Peptide 2 are evaluated using a hemolytic assay, a human RPE cell-based assay, and ultraviolet (UV) absorption properties, respectively, and compared to the respective properties of its parent peptide (Peptide 1).. The sequence of Peptide 2 contains an arginine-serine N-terminal extension (a characteristic of parent Peptide 1) and a novel 8-polyethylene glycol (PEG) block C-terminal extension. Peptide 2 has significantly improved aqueous solubility compared to Peptide 1 and comparable complement inhibitory activity. In addition, Peptide 2 is more efficacious in inhibiting complement activation in a cell-based model that mimics the pathobiology of dry AMD.. We have designed a new peptide analog of compstatin that combines N-terminal polar amino acid extensions and C-terminal PEGylation extensions. This peptide demonstrates significantly improved aqueous solubility and complement inhibitory efficacy, compared to the parent peptide. The new peptide overcomes the aggregation limitation for clinical translation of previous compstatin analogs and is a candidate to become a therapeutic for the treatment of AMD.

Topics: Amino Acid Sequence; Animals; Cell Line; Complement System Proteins; Hemolysis; Humans; Inhibitory Concentration 50; Macular Degeneration; Peptides; Peptides, Cyclic; Rabbits; Solubility

For the past 10 years, number of evidence has shown that activation of complement cascade has been associated with age-related macular degeneration (AMD). The genome wide association study in American population with dominantly dry-type AMD has revealed strong association with single nucleotide polymorphism (SNP) of complement genes. Protein composition of drusen, a deposit observed in sub-retinal space between Bruch's membrane and retinal pigment epithelial (RPE), contains active complement molecules in human and monkey. These evidences have leaded us to consider the possibility of suppressing complement cascade in the retina to delay or reverse the onset of AMD. To test is hypothesis we used the C3 inhibitor Compstatin on primate model with early-onset macular degeneration which develop drusen in less than 2 years after birth. Our preliminary result showed drusen disappearance after 6 months of intravitreal injection.

Topics: Age of Onset; Animals; Complement C3; Complement System Proteins; Disease Models, Animal; Humans; Intravitreal Injections; Macaca fascicularis; Macular Degeneration; Peptides, Cyclic; Retinal Drusen