About the project
Multivalency is a prevalent characteristic of biomolecules that enhances the potency and selectivity of intermolecular interactions through multiple distinct binding interfaces. Nowhere is this better recognised than in the adaptive immune system, where antibodies use multivalency as their key mechanism in responding to infections (both in the dimeric nature of the antigen recognising regions and the symmetry in the Y-shaped structure). Mimicry of this process has resulted in the revolutionary field of antibody therapeutics. However, challenges persist in the field of antibody therapeutics including high production costs, requirement of a unique and accessible antigen, poor thermal and chemical stability, and the variability of the functional outcomes upon antigen recognition, often requiring functional conjugates. Most of these areas are where small molecules excel, with the caveat of being monovalent with limited selectivity, potentially leading to serious side-effects.
Peptides, including disulfide-rich peptide (DRP) toxins derived from animal venoms, offer a compromise in the search for potent and selective molecules. Being intermediate in size, peptides retain some of the expansive interaction surface observed in antibodies, while possessing the high potency and stability characteristics of small molecules. However, their monovalent action constrains receptor avidity and selectivity, limiting the realization of their therapeutic potential. Recently, a new class of bivalent peptide toxins from spider venoms was discovered, resembling antibody architecture and exhibiting remarkable avidity for their receptors. These peptides, collectively termed SCREPs (secreted cysteine-rich repeat proteins), consist of two or more near-identical cysteine-rich peptide domains connected by a short peptide linker. They thus mimic certain architectural features of antibodies, such as high specificity and receptor avidity, while retaining many of the advantageous properties of intermediate size peptides.
By utilizing our SCREP-Yard online database for mining multidomain peptides, novel SCREPs with unique pharmacological properties are being uncovered, including a bivalent insecticidal SCREP in remipede venom that target ryanodine receptors—an important target for pesticides. However, despite the promise of SCREPs as a source of novel multivalent peptides, we have yet to explore in detail their underlying evolution and structural biology.
This project aims to investigate the genomic mechanisms and the structure-function constraints underlying the evolution of multivalency (SCREPs) in animal venoms. We will use a comparative and inter-disciplinary approach to map and characterize SCREPs in various spider lineages, utilizing genomic, proteotranscriptomic, molecular evolution, and structural biology methods. This approach will provide a mechanistic understanding of the evolutionary and structural drivers and constraints of the emergence of multivalency, which is a major contributor to the ability of proteins to evolve new functions. Additionally, by focusing on the often-overlooked interdomain linker regions of SCREPs, which are believed to play a crucial role for the development of multivalency, we will gain functional insight into the structural properties that contribute to multivalency. Ultimately, we aim to leverage the knowledge gained during this project to develop guidelines for designing synthetic bivalent peptides.
Relevant links
Relevant papers:
- Liu J, Maxwell M, Cuddihy T, Crawford T, Bassetti M, Hyde C, Peigneur S, Tytgat J, Undheim EAB, Mobli M (2023) ScrepYard: an online resource for disulfide-stabilised tandem repeat peptides. Protein Science 32(2):e4566. doi: 10.1002/pro.4566
- Maxwell MJ, Undheim EAB, Mobli M (2018) Secreted cysteine-rich repeat proteins “SCREPS”: A novel multi-domain architecture. Frontiers in Pharmacology 9: 1333. doi: 10.3389/fphar.2018.01333
- Maxwell M, Thekkedam C, Lamboley C, Chin YKY, Crawford T, Smith JJ, Liu J, Jia X, Vetter I, Laver D, Launikonis BS, Dulhunty A, Undheim EAB, Mobli M (2023) A bivalent remipede toxin promotes calcium release via ryanodine receptor activation. Nature Communications 14: 1036. doi: 10.1038/s41467-023-36579-w
Financing
The project is currently funded by the Faculty of Mathematics and Natural Sciences at the University of Oslo through its sustainable development initiative.