Lasso grafted Cyclic Peptide Inhibitors of Coagulation Proteases as potential novel therapeutic leads — ASN Events
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  3. Lasso grafted Cyclic Peptide Inhibitors of Coagulation Proteases as potential novel therapeutic leads

Lasso grafted Cyclic Peptide Inhibitors of Coagulation Proteases as potential novel therapeutic leads (#224)

Liam Cavley 1 2 , Dan Ford 1 2 , Charlotte Franck 1 2 , Richard J Payne 1 2
  1. School of Chemistry, The University of Sydney, Camperdown, NSW
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, NSW

Cardiovascular diseases (CVD) continue to be the leading cause of death globally, with an estimated 17.9 million lives being lost every year. The name cardiovascular disease is given to a diverse group of disorders that include, but are not limited to, congenital heart disease, peripheral artery disease and strokes. 80% of the total figure of deaths associated with cardiovascular disease are a result of heart attacks or strokes, with most of these occurring in low to middle income countries. Cerebrovascular diseases (stroke) are also a leading cause of disability, and the number of stroke-related deaths is expected to double by 2050. Antithrombotic therapies play an important part in treating CVD by aiding the body with haemostasis and therefore there is an urgent need for the development of such treatments.

 

Whilst there are currently a range of antithrombotic therapeutics on the market for treating CVD, such as antiplatelet drugs and anticoagulants, the treatments available, although effective under certain settings of CVD, are accompanied with a plethora of issues including major uncontrolled bleeding and large patient variability. The aims of this project are to develop novel treatments for CVD, through the identification of peptide-based antithrombotic therapeutics via mRNA display. These are designed to focus on safer targets, avoiding the unwanted dysregulation in haemostasis associated with those CVD treatments currently on the market. The basis of these drugs will be inhibition of select serine proteases that are involved in blood coagulation.

 

Using the random nonstandard peptides integrated discovery (RaPID) system we have recently identified several cyclic peptides, that target the serine proteases in question, and have combined this with the documented ability to graft cyclic peptides to well-known fragment crystallizable (Fc) domains of antibodies to create constructs with enhanced pharmacokinetics whilst retaining target binding ability. This methodology overcomes many of the complications associated with the administration of cyclic peptides.

  1. World Health Organisation, Cardiovascular Diseases. https://www.who.int/health-topics/cardiovascular- diseases/ (accessed 19/04/2023).
  2. Roth, G. A.; Abate, D.; Abate, K. H.; Abay, S. M.; Abbafati, C.; Abbasi, N.; Abbastabar, H.; Abd-Allah, F.; Abdela, J.; Abdelalim, A., Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 1736-1788. (2018)
  3. Sikka P, Bindra VK. Newer antithrombotic drugs. Indian J Crit Care Med. 188-95 (2010)
  4. Sakai, K., Sugano-Nakamura, N., Mihara, E. et al. Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions. Nat. Biomed. Eng 7, 164–176 (2023).
  5. Daniel J. Ford, Nisharnthi M. Duggan, Richard J. Payne et al. Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming. Journal of Medicinal Chemistry. 7853-7876 (2021)
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