Although the cell permeability of NIP-2 was not very high, we wondered how stable it would be against cellular proteases. Peptides can be highly susceptible to proteolytic degradation, but incorporation of unnatural modifications (e.g.: cyclization, D-amino acids, N-methylation, stapling) enforces stability as these are typically not recognized by proteases. To investigate the effect of the hydrocarbon staple on peptide stability both NIP-WT-Ac and NIP-2-Ac were incubated in HeLa cell lysate and the peptide integrity was monitored by HPLC analysis. Peptide NIP-2-Ac exhibited a 3-fold higher stability (t1/2 = 7.3 h) compared to the equivalent linear version NIP-1-Ac (t1/2 -2.3 h), confirming that hydrocarbon stapling protects against proteolytic cleavage (Fig. , supplemental Fig. ).