Designed Coiled-coil Scaffolds that Mimic NOXA-B. Previously, we have identified NOXA-B residues predicted to contribute to MCL-1 binding. This gives three different binding sequences of varying length: a short motif (S), composed of the centrally clustered residues Leu11, Arg12, Ile14, Asp16 and Val18; a first extended motif (E1), comprising the short motif residues plus Leu4, Leu25 and Asn26; and, a second extended motif (E2) incorporating the E1 residues as well as Glu7, Asn19, and, glutamate and lysine at the positions 2 and 7 to maintain interchain salt bridges within the coiled coil (Table ). The central Gly15 which contacts the surface of MCL-1 and is highly conserved in BH3 sequences, is included in all three motifs. The identified binding motifs have been grafted onto the outer face of the well-characterized de novo designed peptide CC-Di, avoiding substitutions at the a and d heptad positions as these drive coiled-coil assembly. The parallel homodimeric coiled-coil sequences CC-Di_S, CC-Di_E1 and CC-Di_E2 generated display copies of the grafted motifs S, E1 and E2, on both outer faces of the assembly. A parallel hetero-dimeric pair comprising an acidic peptide (CC-Di-A) partnered with basic peptide (CC-Di-B_S) bearing the S motif is also described. These designed coiled coils selectively inhibit the NOXA-B/MCL-1 interaction with a clear positive correlation between potency and the number of hot-spot residues included in the grafted constellation. For the heterodimeric pair, inhibition depends on the presence of both partners in the coiled-coil assembly.