49-й Общий Семинар. Лекция профессора Майкла Гутщева "Дизайн и синтез пептидомиметиков, ингибирующих протеиназы человека"

Serine and cysteine proteases constitute primary targets in drug discovery. In this lecture, different approaches to utilize inhibitors and activity-based probes for the biochemical analysis and kinetic characterization of proteases will be presented.

A typical feature of peptidic inhibitors of cysteine proteases includes an N-capped peptide structure bearing an electrophilic warhead, e.g. a nitrile or vinyl sulfone,¹ in place of the scissile peptide bond. We explored the impact of the CH/N exchange in the P1 position of dipeptide nitriles and have biochemically characterized the novel azadipeptide nitriles as highly potent inhibitors of therapeutically important cathepsins L, S, K and B. Methylation of the peptide bond in azadipeptides leads to the E configuration and hence to atropisomerism due to a restricted rotation around the N-N axis. Related aza-Freidinger lactams have been discovered as conformationally restricted peptidomimetics. In 3-cyano-3-aza-β-amino acid derivatives, the N-cyano group was centrally arranged in the molecule to allow for interactions with the nonprimed and primed binding regions of the target enzymes.²

Matriptase-2, a type II transmembrane serine protease, plays a key role in the human iron homeostasis. Based on the chemotypes of trisymmetric triacylmethane derivatives and phosphono peptides, the development of inhibitors and activity-based probes for matriptases was carried out.³

The design of an FRET-based probe for the serine protease human neutrophil elastase relies on a sulfonyloxyphthalimide moiety, capable to undergo a Lossen rearrangement, as a new type of warhead that is linker-connected to a coumarin fluorophore.⁴


1) J. Med. Chem. 2012, 55, 5982. (b) Org. Biomol. Chem. 2013, 11, 5913.

2) Angew. Chem. Int. Ed. 2008, 47, 4331. (b) Chem. Commun. 2012, 48, 5772. (c) Org. Lett. 2013, 15, 448. (d) ACS Med. Chem. Lett. 2014, 5, 1076 and unpublished results.

3) Chem. Eur. J. 2016, 22, 610. b) Chem. Eur. J. 2016, 22, 8525-8535. c) Chem. Eur. J. 2017, 23, 5205 and unpublished results.

4) Biochemistry 2018, 57, 742.

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20 августа 2018 года