Helical secondary and tertiary motifs are commonly observed as binding epitopes in natural and engineered protein scaffolds. While several strategies have been described to constrain α-helices or reproduce their binding attributes in synthetic mimics, general strategies to mimic tertiary helical motifs remain in their infancy. We recently described a synthetic strategy to develop helical dimers ( J. Am. Chem. Soc. 2015, 137, 11618-11621). We found that replacement of an interhelical salt bridge with a covalent bond can stabilize antiparallel motifs in short sequences. Here we show that the approach can be generalized to obtain antiparallel and parallel dimers as well as trimer motifs. Helical stabilization requires judiciously designed cross-linkers as well as optimal interhelical hydrophobic packing. We anticipate that these mimics would afford new classes of modulators of biological function.
n class="Disease">Helical sean class="Chemical">condary and tertiary motifs are commonly observed as binding epitopes in natural and engineered protein scaffolds. While several strategies have been described to constrain α-helices or reproduce their binding attributes in synthetic mimics, general strategies to mimic tertiary helical motifs remain in their infancy. We recently described a synthetic strategy to develop helical dimers ( J. Am. Chem. Soc. 2015, 137, 11618-11621). We found that replacement of an interhelical salt bridge with acovalent bond can stabilize antiparallel motifs in short sequences. Here we show that the approach can be generalized to obtain antiparallel and parallel dimers as well as trimer motifs. Helical stabilization requires judiciously designed cross-linkers as well as optimal interhelical hydrophobic packing. We anticipate that these mimics would afford new classes of modulators of biological function.
Authors: Christopher W Wood; Marc Bruning; Amaurys Á Ibarra; Gail J Bartlett; Andrew R Thomson; Richard B Sessions; R Leo Brady; Derek N Woolfson Journal: Bioinformatics Date: 2014-07-26 Impact factor: 6.937
Authors: Daniel Y Yoo; Stephanie A Barros; Gordon C Brown; Christian Rabot; Dafna Bar-Sagi; Paramjit S Arora Journal: J Am Chem Soc Date: 2020-08-13 Impact factor: 15.419
Authors: Seong Ho Hong; Daniel Y Yoo; Louis Conway; Khyle C Richards-Corke; Christopher G Parker; Paramjit S Arora Journal: Proc Natl Acad Sci U S A Date: 2021-05-04 Impact factor: 11.205
Authors: Catherine A Hurd; Paul Brear; Jefferson Revell; Sarah Ross; Helen R Mott; Darerca Owen Journal: J Biol Chem Date: 2020-11-23 Impact factor: 5.157