Covalent-reversible peptide-based protease inhibitors. Design, synthesis, and clinical success stories

Feral, Anthony; Martín, Anthony R.; Desfoux, Alexandre; Amblard, Muriel; Vezenkov, Lubomir

doi:10.1007/s00726-023-03286-1

Cited by 2 publications

(1 citation statement)

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“…Despite many warheads not having as much depth for kinetic and mechanistic studies for tuning reactivity for the purpose of designing RCIs, there are many that have been designed to leverage reactivity toward a particular target amino acid residue, such as cysteine, serine/threonine, or lysine, as seen in Figure 5 . The examples include reversible warheads for cysteine such as α-cyanocarbonyls 35 or other α-substituted alkenes with good electron withdrawing groups, 30 , 36 nitriles, 37 aldehydes, 38 and dihaloacetamides 39 (although the halogens are lost, and the equilibrium is between the free cysteine and 2-oxoacetamide), and thiomethyltetrazines; 40 reversible warheads for serine/threonine include α-oxo-amides 41 and boronic acids; 42 and reactive amines such as lysines and N -terminus amines react with aldehydes to form stabilized imines, 43 either by a neighboring hydrogen bond donor, or through subsequent formation of a stable diazaborine. 44 Example compounds for each of these warheads can be seen in Figure 6 .…”

Section: Chemical Characteristics Of Reversible Covalent Warheadsmentioning

confidence: 99%

Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

Patel,

Huma,

Duncan

2024

ACS Chem. Biol.

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Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading to covalent adducts, there has been success in developing covalent inhibitors, especially within the field of anticancer therapy. Covalent inhibitors can have an advantage over noncovalent inhibitors since the formation of a covalent adduct may serve as an additional mode of selectivity due to the intrinsic reactivity of the target protein that is absent in many other proteins. Unfortunately, many covalent inhibitors form irreversible adducts with off-target proteins, which can lead to considerable side-effects. By designing the inhibitor to form reversible covalent adducts, one can leverage competing on/off kinetics in complex formation by taking advantage of the law of mass action. Although covalent adducts do form with off-target proteins, the reversible nature of inhibition prevents accumulation of the off-target adduct, thus limiting side-effects. In this perspective, we outline important characteristics of reversible covalent inhibitors, including examples and a guide for inhibitor development.

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