Chemical synthesis and characterisation of the complement C5 inhibitory peptide zilucoplan

Targeting protein-protein interactions (PPIs) has been recently recognized as an emerging therapeutic approach for several diseases. Up today, more than half a million PPI dysregulations have been found to be involved in pathological events. The dynamic nature of these processes and the involvement of large protein surfaces discouraged anyway the scientific community in considering them promising therapeutic targets. More recently peptide drugs received renewed attention since drug discovery has offered a broad range of structural diverse sequences, moving from traditionally endogenous peptides to sequences possessing improved pharmaceutical profiles. About 70 peptides are currently on the marked but several others are in clinical development. In this review we want to report the update on these novel APIs, focusing our attention on the molecules in clinical development, representing the direct consequence of the drug discovery process of the last 10 years. The comprehensive collection will be classified in function of the structural characteristics (native, analogous, heterologous) and on the basis of the therapeutic targets. The mechanism of interference on PPI will also be reported to offer useful information for novel peptide design.

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“…Zilucoplan also inhibits the interaction between C5b and C6, thereby further blocking MAC assembly. (Gorman et al, 2021;Duda et al,2020).…”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Cabri

Cantelmi

Corbisiero

et al. 2021

Front. Mol. Biosci.

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“…Nomacopan (Akari), a tick-derived protein inhibitor with dual activity for C5 and leukotriene B4 [ 105 ], is in phase 3 trials for pediatric HSCT-TMA with another phase 3 trial for the autoimmune disease bullous pemphigoid in preparation. The macrocyclic peptide zilucoplan (UCB) [ 106 ], on the other hand, has entered phase 3 trials for gMG; similar to crovalimab in PNH, zilucoplan may confer a benefit over current anti-C5 therapy in gMG by allowing for patient self-administration [ 107 ]. Of note, zilucoplan did not show meaningful efficacy in phase 2 trials for immune-mediated necrotizing myopathy [ 108 ], which indicates that not all autoimmune disorders benefit from C5- or even complement-targeted therapy.…”

Section: One Size Does Not Fit All: Extended Options In Therapeutic Complement Modulationmentioning

confidence: 99%

Tipping the balance: intricate roles of the complement system in disease and therapy

Pouw

Ricklin

2021

Semin Immunopathol

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The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is indispensable for its role as host defense and surveillance system. However, the danger sensing versatility of complement may come at a steep price for patients suffering from various immune, inflammatory, age-related, or biomaterial-induced conditions. Misguided recognition of cell debris or transplants, excessive activation by microbial or damaged host cells, autoimmune events, and dysregulation of the complement response may all induce effector functions that damage rather than protect host tissue. Although complement has long been associated with disease, the prevalence, impact and complexity of complement’s involvement in pathological processes is only now becoming fully recognized. While complement rarely constitutes the sole driver of disease, it acts as initiator, contributor, and/or exacerbator in numerous disorders. Identifying the factors that tip complement’s balance from protective to damaging effects in a particular disease continues to prove challenging. Fortunately, however, molecular insight into complement functions, improved disease models, and growing clinical experience has led to a greatly improved understanding of complement’s pathological side. The identification of novel complement-mediated indications and the clinical availability of the first therapeutic complement inhibitors has also sparked a renewed interest in developing complement-targeted drugs, which meanwhile led to new approvals and promising candidates in late-stage evaluation. More than a century after its description, complement now has truly reached the clinic and the recent developments hold great promise for diagnosis and therapy alike.

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“… n.s. Preclinical Biovitrum Zilucoplan and Zilucoplan-XR Peptide SC PNH; myasthenia gravis II; III UCB [ 118 ] Tesidolumab (LFG316) Monoclonal antibody IVT or IV Age-related macular degeneration; PNH II Novartis, NCT02534909,NCT01527500 Cemdisiran (ALN-CC5) RNAi SC PNH; aHUS II Alnylam [ 119 ] C5a Vilobelimab (IFX-1; CaCP29) Monoclonal antibody IV Hidradenitis suppurativa; ANCA-associated vasculitis; severe COVID-19 pneumonia; pyoderma gangrenosum; granulomatosis with polyangitis; microscopic polyangiitis; sepsis; systemic inflammatory response syndrome II; III for COVID-19 pneumonia InflaRx [ 120 ] IFX-2 Monoclonal antibody IV n.s. Preclinical InflaRX C5aR Avdoralimab Monoclonal antibody IV COVID-19; bullous pemphigoid; advanced solid and hematological tumors II Innate Pharma, NCT04371367,NCT04563923,NCT04333914 Avacopan Small molecular antagonist Oral aHUS; ANCA-associated vasculitis II; III ChemoCentryx [ 121 , 122 ] C6 Regenemab (CP010) Monoclonal antibody n.s.…”

Section: Complement Inhibition Nowadays and In The Futurementioning

confidence: 99%

“…Although their clinical effect and application are probably similar to that of the currently approved therapeutics, these new therapeutics are designed to simplify the administration, which will increase convenience and compliance to therapy and may reduce costs. Coversin, crovalimab, zilucoplan, and cemdisiran (all in phase II trials) are all C5 inhibitors that can be administered subcutaneously [ 57 , 116 , 118 , 119 ]. Lastly, aurintricarboxylic acid is a C9 small molecule inhibitor that can be taken orally and was effective in inhibiting hemolysis of PNH RBCs in vitro [ 123 , 145 ].…”

Section: Complement Inhibition Nowadays and In The Futurementioning

confidence: 99%

Halting targeted and collateral damage to red blood cells by the complement system

et al. 2021

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The complement system is an important defense mechanism against pathogens; however, in certain pathologies, the system also attacks human cells, such as red blood cells (RBCs). In paroxysmal nocturnal hemoglobinuria (PNH), RBCs lack certain complement regulators which sensitize them to complement-mediated lysis, while in autoimmune hemolytic anemia (AIHA), antibodies against RBCs may initiate complement-mediated hemolysis. In recent years, complement inhibition has improved treatment prospects for these patients, with eculizumab now the standard of care for PNH patients. Current complement inhibitors are however not sufficient for all patients, and they come with high costs, patient burden, and increased infection risk. This review gives an overview of the underlying pathophysiology of complement-mediated hemolysis in PNH and AIHA, the role of therapeutic complement inhibition nowadays, and the high number of complement inhibitors currently under investigation, as for almost every complement protein, an inhibitor is being developed. The focus lies with novel therapeutics that inhibit complement activity specifically in the pathway that causes pathology or those that reduce costs or patient burden through novel administration routes.

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Chemical synthesis and characterisation of the complement C5 inhibitory peptide zilucoplan

Cited by 20 publications

References 23 publications

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Tipping the balance: intricate roles of the complement system in disease and therapy

Halting targeted and collateral damage to red blood cells by the complement system

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