Serine and Threonine β-Lactones: A New Class of Hepatitis A
Virus 3C Cysteine Proteinase Inhibitors
Manjinder S. Lall
Yeeman K. Ramtohul
Michael N. G. James
John C. Vederas
10.1021/jo0109016.s001
https://acs.figshare.com/articles/journal_contribution/Serine_and_Threonine_-Lactones_A_New_Class_of_Hepatitis_A_Virus_3C_Cysteine_Proteinase_Inhibitors/3690573
Hepatitis A virus (HAV) 3C enzyme is a cysteine proteinase essential for viral replication and
infectivity and represents a target for the development of antiviral drugs. A number of serine and
threonine β-lactones were synthesized and tested against HAV 3C proteinase. The d-<i>N</i>-Cbz-serine
β-lactone <b>5a</b> displays competitive reversible inhibition with a <i>K</i><sub>i</sub> value of 1.50 × 10<sup>-6</sup> M. Its
enantiomer, l-<i>N</i>-Cbz-serine β-lactone <b>5b</b> is an irreversible inactivator with <i>k</i><sub>inact</sub> = 0.70 min<sup>-1</sup>, <i>K</i><sub>Ι</sub>
= 1.84 × 10<sup>-4</sup> M and <i>k</i><sub>inact</sub>/<i>K</i><sub>Ι</sub> = 3800 M<sup>-1</sup> min<sup>-1</sup>. Mass spectrometry and HMQC NMR studies
using <sup>13</sup>C-labeled <b>5b</b> show that inactivation of the enzyme occurs by nucleophilic attack of the
cysteine thiol (Cys-172) at the β-position of the oxetanone ring. Although the <i>N</i>-Cbz-serine β-lactones
<b>5a </b>and<b> 5b </b>display potent inhibition, other related analogues with an <i>N</i>-Cbz side chain, such as the
five-membered ring homoserine γ-lactones <b>14a</b> and <b>14b</b>, the four-membered ring β-lactam <b>33</b>,
2-methylene oxetane <b>34</b>, cyclobutanone <b>36</b>, and 3-azetidinone <b>39</b>, fail to give significant inhibition
of HAV 3C proteinase, thus demonstrating the importance of the β-lactone ring for binding.
2002-02-05 00:00:00
oxetanone ring
nucleophilic attack
k inact
inhibition
cysteine thiol
5 b display
mass spectrometry
lactone
New Class
K Ι
Cbz side chain
14 b
K i value
HAV 3 C proteinase
3 C enzyme
cysteine proteinase
Virus 3 C Cysteine Proteinase Inhibitors Hepatitis
3800 M
cyclobutanone 36
0.70 min
HMQC NMR studies