Screening, Synthesis and Biochemical Characterization of SARS-CoV-2 Protease Inhibitors
Abstract
:1. Introduction
2. Results
2.1. Naphthalene-Based PLpro and Mpro Inhibitors
- (i)
- substituents at the 4- position on the thiazole ring (compounds 4–12);
- (ii)
- substituents at the 4,5 positions on the thiazole ring (compounds 13–24);
- (iii)
- replacing the naphthalene group of compound 3 with the 4-methyl- or 4-aminophenyl group and introducing different substituents at the 4,5 positions of the thiazole ring (compounds 25–31).
2.2. Disulfide Derivatives as PLpro and Mpro Inhibitors
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.2. Protein Expression and Purification
4.3. Fluorescence Thermal Shift Assay (FTSA)
4.4. Enzymatic Inhibition Assay
4.5. Mass Spectrometry
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | Kd, µM | |||
---|---|---|---|---|
PLpro | Mpro | |||
1 | 68 | >200 | ||
2 | 29 | >200 | ||
3 | 14 | 25 | ||
R1 group | 4 | 110 | >200 | |
5 | >200 | >200 | ||
6a | 50 | >200 | ||
6b | 50 | >200 | ||
6c | 50 | >200 | ||
6d | 25 | 26 | ||
6e | 20 | >200 | ||
7 | 50 | >200 | ||
8 | 35 | >200 | ||
9 | 50 | >200 | ||
10 | 35 | >200 | ||
11 | >200 | >200 | ||
12 | 29 | >200 | ||
R2 group | Short tail | 13a | 24 | 6.5 |
13b | 50 | >200 | ||
13c | 8.6 | 8.6 | ||
14 | 9.2 | >200 | ||
15 | 50 | >200 | ||
16 | 50 | >200 | ||
17 | >200 | >200 | ||
18 | 50 | >200 | ||
19 | 50 | >200 | ||
20 | 29 | >200 | ||
Long tail | 21a | 110 | >200 | |
21b | 29 | 17 | ||
21c | 52 | >200 | ||
22 | 5.2 | 10 | ||
23 | 75 | >200 | ||
24 | 8.0 | >200 | ||
Two tails/ scaffold variation group | 25a | 83 | >200 | |
25b | 66 | >200 | ||
25c | 58 | >200 | ||
26 | 16 | >200 | ||
27a | 35 | >200 | ||
27b | 50 | >200 | ||
27c | 15 | >200 | ||
28 | 8.8 | 50 | ||
29 | >200 | >200 | ||
30a | 50 | >200 | ||
30b | 50 | >200 | ||
30c | 32 | >200 | ||
30d | 50 | >200 | ||
31 | 50 | 50 | ||
GRL0617 | 1.6 | >200 |
Compound | Kd, µM | |
---|---|---|
PLpro | Mpro | |
32 | 0.54 | 2.8 |
33 | 2.0 | >200 |
34 | 0.43 | 3.5 |
35 | 2.5 | >200 |
36 | 1.9 | >200 |
37 | 0.63 | >200 |
38 | 1.9 | >200 |
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Bagdonas, M.; Čerepenkaitė, K.; Mickevičiūtė, A.; Kananavičiūtė, R.; Grybaitė, B.; Anusevičius, K.; Rukšėnaitė, A.; Kojis, T.; Gedgaudas, M.; Mickevičius, V.; et al. Screening, Synthesis and Biochemical Characterization of SARS-CoV-2 Protease Inhibitors. Int. J. Mol. Sci. 2023, 24, 13491. https://doi.org/10.3390/ijms241713491
Bagdonas M, Čerepenkaitė K, Mickevičiūtė A, Kananavičiūtė R, Grybaitė B, Anusevičius K, Rukšėnaitė A, Kojis T, Gedgaudas M, Mickevičius V, et al. Screening, Synthesis and Biochemical Characterization of SARS-CoV-2 Protease Inhibitors. International Journal of Molecular Sciences. 2023; 24(17):13491. https://doi.org/10.3390/ijms241713491
Chicago/Turabian StyleBagdonas, Martynas, Kamilė Čerepenkaitė, Aurelija Mickevičiūtė, Rūta Kananavičiūtė, Birutė Grybaitė, Kazimieras Anusevičius, Audronė Rukšėnaitė, Tautvydas Kojis, Marius Gedgaudas, Vytautas Mickevičius, and et al. 2023. "Screening, Synthesis and Biochemical Characterization of SARS-CoV-2 Protease Inhibitors" International Journal of Molecular Sciences 24, no. 17: 13491. https://doi.org/10.3390/ijms241713491