Table 1. Summary of nirmatrelvir and ensitrelvir resistance phenotypes of SARS2 Mpro variants tested in the live-cell gain-of-signal assay.
Mpro variant | Frequency in GISAID | Nirmatrelvir | Ensitrelvir | |||
---|---|---|---|---|---|---|
Pre-Omicron | Omicron-present | IC50 nM (95% CI) | Fold resistance (relative to WT) | IC50 nM (95% CI) | Fold resistance (relative to WT) | |
WT | – | – | 31.6 | – | 23.0 | – |
(26.1–37.7) | (20.4–25.9) | |||||
T45I | 3.5 × 10−4 | 4.8 × 10−5 | 64.2 | ~2 | 111 | 4.1 |
(46.2–85.7) | (92.4–132) | |||||
S46F | 4.1 × 10−4 | 1.1 × 10−4 | 34.5 | <2 | 34.5 | <2 |
(28.3–41.5) | (28.3–41.5) | |||||
E47K | 1.2 × 10−4 | 7.6 × 10−6 | 27.3 | <2 | 17.4 | <2 |
(10.0–44.3) | (12.8–21.8) | |||||
D48Y | 1.4 × 10−5 | 1.6 × 10−6 | 62.7 | ~2 | 135 | 5.0 |
(44.0–88.9) | (99.3–184) | |||||
M49I | 2.5 × 10−4 | 2.3 × 10−5 | 33.5 | <2 | 335 | 12.4 |
(20.6–46.7) | (197–664) | |||||
M49L | 6 × 10−5 | 7.5 × 10−7 | 21.2 | <2 | 436 | 25.4 |
(17.1–25.9) | (38–573) | |||||
M49T | 1 × 10−5 | – | 11.1 | <2 | 69.0 | 4.0 |
(10.2–12.1) | (63.3–75.2) | |||||
M49V | 4.7 × 10−6 | 3.7 × 10−6 | 7.9 | <2 | 44.5 | 2.6 |
(7.0–8.9) | (38.2–51.7) | |||||
S144A | 1.3 × 10−6 | 6.5 × 10−7 | 267 | 12.2 | 395 | 16.9 |
(215–334) | (304–523) | |||||
M165I | 1.2 × 10−5 | 4.2 × 10−6 | 29.9 | <2 | 49.3 | ~2 |
(22.4–39.5) | (33.3–67.2) | |||||
P168S | 5.1 × 10−5 | 2 × 10−5 | 19.9 | <2 | 36.4 | <2 |
(15.5–25.0) | (30.1–43.6) | |||||
∆P168 | 9.5 × 10−6 | 1.6 × 10−7 | 180 | 5.1 | 157 | 6.8 |
(154–219) | (132–188) | |||||
T169I | 5.1 × 10−5 | 9.2 × 10−6 | 34.0 | <2 | 30.9 | <2 |
(23.7–45.0) | (24.1–38.7) | |||||
V171I | 5.3 × 10−5 | 2.8 × 10−5 | 21.1 | <2 | 33.4 | <2 |
(13.6–28.3) | (26.4–41.2) | |||||
A173V | 1.8 × 10−5 | 1.0 × 10−5 | 328 | 11.6 | 29.6 | <2 |
(186–796) | (24.2–35.4) | |||||
A173T | 1.2 × 10−5 | 2.4 × 10−5 | 77.6 | 4.1 | 28.3 | <2 |
(104–132) | (24.0–33.1) | |||||
A173S | 1.1 × 10−5 | 1.3 × 10−6 | 18.6 | <2 | 26.2 | <2 |
(15.9–21.2) | (22.3–30.5) | |||||
∆P168/A173V | – | – | 1510 | 51 | 90.5 | 2.8 |
(1380–1660) | (80.9–102) | |||||
T45I/M49L | – | – | 20.8 | <2 | 1030 | 54.5 |
(16.4–25.6) | (814–1340) | |||||
T45I/A173V | – | – | 414 | 20.6 | 79.2 | 4.2 |
(351–494) | (66.4–94.7) | |||||
D48Y/∆P168 | – | – | 921 | 45.9 | 754 | 39.9 |
(732–1220) | (676–857) | |||||
M49I/∆P168 | – | – | 151 | 7.5 | 990 | 52.5 |
(11.9–210) | (772–1310) | |||||
M49L/∆P168 | – | – | 144 | 7.2 | 2400 | 127 |
(129–162) | (1890–3110) |