Biochemical and Biophysical Research Communications, Vol.526, No.2, 349-354, 2020
Incorporation of alpha-methylated amino acids into Apolipoprotein A-I mimetic peptides improves their helicity and cholesterol efflux potential
Apolipoprotein A-I (ApoA-I) mimetic peptides are potential therapeutic agents for promoting the efflux of excess cellular cholesterol, which is dependent upon the presence of an alpha-mphipathic helix. Since alpha-methylated Ala enhances peptide helicity, we hypothesized that incorporating other types of alpha-methylated amino acids into ApoA-I mimetic peptides may also increase their helicity and cholesterol efflux potential. The last helix of apoA-I, peptide 'A' (VLESFKVSFLSALEEYTKKLNT), was used to design peptides containing a single type of alpha-methylated amino acid substitution (Ala/A(alpha), Glu/D-alpha, Lys/K-alpha, Leu/L-alpha), as well as a peptide containing both alpha-methylated Lys and Leu (6(alpha)). Depending on the specific residue, the ahelical content as measured by CD-spectroscopy and calculated hydrophobic moments were sometimes higher for peptides containing other types of alpha-methylated amino acids than those with alpha-methylated Ala. In ABCAl-transfected cells, cholesterol efflux to the peptides showed the following order of potency: 6(alpha)>K-a approximate to L-a approximate to A(alpha) approximate to D-alpha approximate to A. In general, alpha-methylated peptides were resistant to proteolysis, but this varied depending on the type of protease and specific amino acid substitution. In summary, increased helicity and amphilicity due to alpha-methylated amino acid substitutions in ApoA-I mimetic peptides resulted in improved cholesterol efflux capacity and resistance to proteolysis, indicating that this modification may be useful in the future design of therapeutic ApoA-I mimetic peptides. Published by Elsevier Inc.