Structural examination of ring-closing metathesis-derived 15-member macrocycles as Grb2 SH2 domain-binding tetrapeptide mimetics.
Ring-closing metathesis (RCM) was employed to join carboxy-terminal alkenyl glycine side chains together with vinyl- and allyl-functionality appended to the beta-methylene of amino-terminal phosphotyrosyl (pTyr) mimetics. This required the synthesis of a variety of new pTyr mimetics, including a novel aza-containing analogue. Many of the resulting 15-member macrocyclic tetrapeptide mimetics exhibited low nanomolar Grb2 SH2 domain-binding affinities in spite of the fact that differing ring junction stereochemistries and geometries of the RCM-derived double bond were employed. The finding that significant latitude exists in the structural requirements for ring closure may facilitate the development of therapeutically relevant macrocyle-based Grb2 SH2 domain-binding antagonists. The synthetic approaches used in this study may also find application to peptide mimetics directed at other biological targets.
Liu
Fa
F
Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Frederick, Maryland 21702, USA.
Worthy
Karen M
KM
Bindu
Lakshman K
LK
Fisher
Robert J
RJ
Burke
Terrence R
TR
D001665:Binding Sites; D003500:Cyclization; D051380:GRB2 Adaptor Protein / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry*; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism; D018909:src Homology Domains
D051380:GRB2 Adaptor Protein; D047028:Macrocyclic Compounds; D009842:Oligopeptides