145038-53-5Relevant articles and documents
Controlled Inhibition of Apoptosis by Photoactivatable Caspase Inhibitors
Chakrabarty, Suravi,Verhelst, Steven H.L.
, p. 1434 - 10,1440 (2020)
Caspases control regulated cell death (apoptosis), a process that is crucial in the development of multicellular organisms as well as in various diseases. In order to spatiotemporally study apoptosis, we here develop photoactivatable caspase inhibitors. These are based on cysteine-reactive acyloxymethyl ketone electrophiles connected to a peptide targeting caspases. Importantly, the aspartate crucial for recognition by caspases is caged with a photoprotecting group. Ester photocages were found to be labile, and it was critical to have a nitroindoline cage, which forms a stable amide bond with the aspartate side chain. The nitroindoline-protected inhibitors lead to an efficient turn-on of inhibitory activity after irradiation with light. They are applicable in live cells, where they prevent anti-FAS-induced apoptosis only upon irradiation. Overall, these reagents will allow a better understanding of the spatial and temporal dimensions of apoptosis in complex, dynamic systems.Activation of caspases leads to apoptosis. Chakrabarty and Verhelst designed, synthesized, and evaluated photocaged caspase inhibitors that allow caspase inhibition only upon irradiation with light. These reagents allow for a precise spatial and temporal control over caspase inhibition and may be used to study apoptosis in space and time.
Positional scanning for peptide secondary structure by systematic solid-phase synthesis of amino lactam peptides
Jamieson, Andrew G.,Boutard, Nicolas,Beauregard, Kim,Bodas, Mandar S.,Ong, Huy,et al.
supporting information; experimental part, p. 7917 - 7927 (2009/10/16)
Incorporation of amino lactams into biologically active peptides has been commonly used to restrict conformational mobility, enhance selectivity, and increase potency. A solid-phase method using a Fmoc-protection strategy has been developed for the systematic synthesis of peptides containing configurationally defined α- and β-amino γ-lactams. N-Alkylation of N-silyl peptides with five- and six-member cyclic sulfamidates 9 and 8 minimized bis-alkylation and provided N-alkyl peptides,which underwent lactam annulation under microwave heating. Employing th is solid-phase protocol on the growth hormone secretagogue GHRP-6, as well as on the allosteric modulator of the IL-1 receptor 101.10, has furnished 16 lactam derivatives and validated the effectiveness of this approach on peptides bearing aliphatic, aromatic, branched, charged, and heteroatomic side chains. The binding affinity IC 50 values of the GHRP-6 lactam analogues on both the GHS-R1a and CD36 receptors are reported as well as inhibition of thymocyte proliferation measurements for the 101.10 lactam analogues. In these cases, lactam analogues were prepared exhibiting similar or improved properties compared with the parent peptide. Considering the potential for amino lactams to induce peptide turn conformations, the effective method described herein for their supported construction on growing peptides, and for the systematical amino lactam scan of peptides, has proven useful for the rapid identification of the secondary structure necessary for peptide biological activity.
