TY - JOUR

T1 - A glutamine-based single α-helix scaffold to target globular proteins

AU - Escobedo, Albert

AU - Piccirillo, Jonathan

AU - Aranda, Juan

AU - Diercks, Tammo

AU - Mateos, Borja

AU - Garcia-Cabau, Carla

AU - Sanchez-Navarro, Macarena

AU - Topal, Busra

AU - Biesaga, Mateusz

AU - Staby, Lasse

AU - Kragelund, Birthe B.

AU - Garcia, Jesus

AU - Millet, Oscar

AU - Orozco, Modesto

AU - Coles, Murray

AU - Crehuet, Ramon

AU - Salvatella, Xavier

PY - 2022

Y1 - 2022

N2 - The binding of intrinsically disordered proteins to globular ones can require the folding of motifs into α-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single α-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single α-helices for a wide range of applications in protein engineering and drug design.Targeting biomedically relevant protein-protein interactions is a long-lasting challenge in medicinal chemistry. Here, the authors develop a single α-helical peptide scaffold that can be tailored to target globular proteins of biomedical interest.

AB - The binding of intrinsically disordered proteins to globular ones can require the folding of motifs into α-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single α-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single α-helices for a wide range of applications in protein engineering and drug design.Targeting biomedically relevant protein-protein interactions is a long-lasting challenge in medicinal chemistry. Here, the authors develop a single α-helical peptide scaffold that can be tailored to target globular proteins of biomedical interest.

KW - HUNTINGTIN EXON-1

KW - NMR-SPECTROSCOPY

KW - CHEMICAL-SHIFTS

KW - TERMINAL DOMAIN

KW - FORCE-FIELD

KW - RANDOM COIL

KW - PEPTIDE

KW - DYNAMICS

KW - INHIBITORS

KW - ASSIGNMENT

U2 - 10.1038/s41467-022-34793-6

DO - 10.1038/s41467-022-34793-6

M3 - Journal article

C2 - 36400768

VL - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 7073

ER -