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. Author manuscript; available in PMC: 2020 Jul 14.
Published in final edited form as: J Am Chem Soc. 2020 Feb 4;142(7):3351–3355. doi: 10.1021/jacs.9b13405

Table 1.

Inhibition of γ-secretase by helical peptide/transition-state analogue conjugates.

Cmpd Helical Peptide Linker Transition-State Analoguea IC50b
APP transmembrane residues 707–717: --------Optimized TSA-----------
---Val-Gly-Gly-Val-Val-Ile-Ala-Thr-Val-Ile---- ----P2 - P1 - P1′- P2′-P3′-----
1 Boc-Val-Phe-ψ-Phe-Leu-Val-NH2 41 ± 4
2 Boc-Val-Gly-Aib-Val-Val-Ile-Aib-Phe-Val-Aib-OCH3 58 ± 6
3 Boc-Val-Gly-Aib-Val-Val-Ile-Aib-Phe-Val-Aib- - -Val-Phe-ψ-Phe-Leu-Val-NH2 53 ± 1
4 Boc-Val-Gly-Aib-Val-Val-Ile-Aib-Phe-Val-Aib- -NH(CH2)2CO- -Val-Phe-ψ-Phe-Leu-Val-NH2 12 ± 2
5 Boc-Val-Gly-Aib-Val-Val-Ile-Aib-Phe-Val-Aib- -NH(CH2)4CO- -Val-Phe-ψ-Phe-Leu-Val-NH2 10 ± 1
6 Boc-Val-Gly-Aib-Val-Val-Ile-Aib-Phe-Val-Aib- -NH(CH2)8CO- -Val-Phe-ψ-Phe-Leu-Val-NH2 0.80 ± 0.03
7 - BocNH(CH2)8CO- -Val-Phe-ψ-Phe-Leu-Val-NH2 16 ± 1
8 Boc-Val-Gly-Aib-Val-Val-Ile-Aib-Phe-Val-Aib- -NH(CH2)8CO- -Val-Phe - Phe-Leu-Val-NH2 18 ± 3
9 Boc-Val-Gly-Aib-DVal-D Val-Ile-Aib-Phe-Val-Aib- -NH(CH2)8CO- -Val-Phe-ψ-Phe-Leu-Val-NH2 6 ± 2
a

ψ represents hydoxyethylurea replacement of peptide backbone;

b

concentration that inhibits 50% activity of 1 nM purified γ-secretase