Protein-protein interactions (PPIs) control and regulate many biological processes including cell signaling, homeostasis and immune response. Modulation of PPIs offers significant therapeutic potential. Indeed, there has been progress in developing small molecules, antibodies and peptides for neurodegenerative disorders, inflammatory diseases and cancer. However, it remains challenging to develop orthosteric inhibitors of PPIs, as recognition typically occurs across a large surface area that often lacks the structurally well-defined pockets that are the hallmark of ligand binding sites. Peptides are a promising class of PPI inhibitors. They offer extended and structurally diverse three-dimensional surfaces that can be endowed with amino acid-based recognition handles to confer the necessary target binding affinity and selectivity. Their straightforward synthesis and purification, potential for chemical modification or stabilization, and crucially their ability to mimic a native binding partner with high fidelity have stimulated interest in their use as PPI inhibitors. Lastly, significant developments in protein design have made possible the design of stable and soluble scaffolds for presenting binding epitopes. Coiled-coil peptide assemblies in particular are inherently stable, highly modular, and well-understood scaffolds. Coiled-coil sequences have distinctive (abcdefg)n heptad repeats where the a and d positions are usually occupied by hydrophobic residues to promote the association of two or more α-helical peptides. Such helical bundles can present binding motifs in spatially defined manners on the outer surfaces of the assemblies for instance at the solvent-exposed b, c and f positions. These scaffolds have been exploited in numerous settings including: rewiring signaling pathways, regulating signaling, delivery, and as therapeutic candidates. Moreover coiled-coil oligomers offer a robust platform to achieve multivalent or co-operative binding. Multiple binding sites can improve potency through avidity and induce signaling events by colocalization: many natural processes harness multivalency and designed synthetic reagents have sought to employ it to improve biological efficacy. Also, positive co-operative binding may occur where ligand binding increases the affinity of subsequent ligand binding events. Previously, we have described the use of coiled coils as scaffolds for inhibition of helix-mediated PPIs. In that work, clusters of hot-spot residues from NOXA-B are grafted onto parallel homo-and heterodimeric coiled coils, which selectively inhibit the interaction of BH3 ligands with MCL-1. MCL-1 is a member of the B-cell lymphoma 2 (BCL-2) family of proteins. This family regulates apoptosis through interactions between pro-and anti-apoptotic members. Therefore, MCL-1 has been the focus of drug discovery efforts. Here we explore further coiledcoil scaffolds including homotrimeric and tetrameric coiled coils alongside a monomeric control peptide to investigate the interplay between MCL-1 inhibitory potency and coiled-coil assembly (Fig. ). Using a combination of AlphaFold2 modelling, fluorescence anisotropy, circular dichroism (CD) spectroscopy, native mass spectrometry, size-exclusion chromatography (SEC) and analytical ultracentrifugation (AUC), we show that the homodimeric coiled coil is the optimal scaffold for these designed inhibitors targeting MCL-1. Binding occurs with 1:1 peptide:protein stoichiometry (i.e., each coiled-coil dimer binds two protein targets), and it is co-operative leading to mutual stabilization of both the coiled-coil scaffold and the target protein. The ability to recruit a binding partner for each recognition surface of the coiled coil opens the path towards future design of multi-specific molecules that can act as "molecular glues" for ternary complex formation. 46 , and is used to generate 'hot-spot' grafted scaffolds representing a monomeric peptide, and homo-and heterodimeric, homotrimeric, and homotetrameric coiled coils.