Proteomimetics as protein-inspired scaffolds with defined tertiary folding patterns

Abstract

Proteins have evolved as a variable platform that provides access to molecules with diverse shapes, sizes and functions. These features have inspired chemists for decades to seek artificial mimetics of proteins with improved or novel properties. Such work has focused primarily on small protein fragments, often isolated secondary structures; however, there has lately been a growing interest in the design of artificial molecules that mimic larger, more complex tertiary folds. In this Perspective, we define these agents as 'proteomimetics' and discuss the recent advances in the field. Proteomimetics can be divided into three categories: protein domains with side-chain functionality that alters the native linear-chain topology; protein domains in which the chemical composition of the polypeptide backbone has been partially altered; and protein-like folded architectures that are composed entirely of non-natural monomer units. We give an overview of these proteomimetic approaches and outline remaining challenges facing the field.

Figure 1 |. Overview of protein structures and their mimetics.

a, Hierarchy of peptide and protein structure, which spans in complexity from primary sequence (light blue) to folded secondary structure (blue) and tertiary structure (tan). b, Corresponding hierarchy of peptide and protein mimetics. Peptidomimetics encompass agents that recreate primary sequence or isolated secondary structure and can be broadly classified into small molecules, peptides containing chemical modification (e.g., macrocyclization shown), or artificial backbones with defined folds (“foldamers”). Proteomimetics, the focus of this Perspective, comprise agents that recreate protein tertiary structure and can be classified into molecules with altered chain topology, partially artificial backbone compositions, or completely artificial backbone compositions. Example peptidomimetic and proteomimetic structures are shown with non-natural parts highlighted in red. (Coordinates for structures from PDB entries 1A46, 1IJA, 1T3R, 1UBQ, 2AGH, 2QMT, 2YJ1, 2YXJ, 3OXC, 4N5T, 5KVN; CSD entry 697088; and references^,.)

Figure 2 |. Examples of proteomimetics based on altered chain topology.

a, Overview of bridging moieties including linker structures resulting from reactions of biselectrophilic crosslinkers or non-natural amino acids with cysteine (1, 2, 3, 4, 7, 8), symmetric trivalent bridges used to crosslink three cysteine residues (5, 9) and a linker resulting from a ring-closing metathesis between two modified asparagine residues (6). b, Model of the INCYPRO stabilized KIX domain based on an NMR structure of the unmodified protein (PDB 2AGH). c, NMR structure of a chemically dimerized parallel coiled-coil. d, NMR structure (PDB 5V2G) of the de novo designed tricyclic three-helix CovCore structure. Proteins are depicted in cartoon representation with hydrophobic core residues shown as sticks (grey). Crosslinks are highlighted (red) and shown as sticks.

Figure 3 |. Examples of proteomimetics based on partially artificial backbone compositions.

a, Chemical structures of selected residue types used to construct modified protein backbones. b-g Experimentally determined folded structures of modified-backbone proteomimetics. Native l-α-residues are shown in grey and non-natural monomers in red. Each panel is labeled with the domain mimicked and a list of residue types in the chain. b, NMR structure of a zinc finger domain mimic with an artificial helix (PDB 5N14). c, Crystal structure of a trimeric assembly formed by a sequence derived from Aβ with turn-inducing and sheet-disrupting modifications (PDB 4NTR). d, NMR structure of a knottin mimic with a heterochiral backbone comprising a d-α-peptide core and native loop. e, NMR structure of a zinc finger domain mimic with backbone modifications in the helix and hairpin regions (PDB 5US3). f, Crystal structure of a helix-turn-helix scaffold modified in the helices (PDB 4WPB). g NMR structure of a de novo disulfide-rich scaffold harboring modifications throughout the helix, loop, turn, and sheet (PDB 6E5J).

Figure 4 |. Examples of proteomimetics based on entirely artificial backbone compositions.

a-b, Crystal structures of an octameric helix bundle assembly formed by a β³-peptide (a) and a hexameric helix bundle assembly formed by an urea oligomer (b); structures are colored by chain. c, Chemical structures of monomers used in the construction of aromatic oligoamide foldamers. d, Crystal structure of fructose (yellow) in complex with an aromatic oligoamide helical capsule. e, Crystal structure of an aromatic oligoamide helix-turn-helix motif.