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. 2023 Mar 29;9(13):eade8778. doi: 10.1126/sciadv.ade8778

Table 1. Summary of nirmatrelvir and ensitrelvir resistance phenotypes of SARS2 Mpro variants tested in the live-cell gain-of-signal assay.

Fold resistance for each mutant tested was calculated on the basis of relative IC50 in the live-cell gain-of-signal assay versus WT in assays ran in parallel to limit potential variability due to transfection efficiency. Frequency of variants based on sequences deposited in the GISAID database as of 10 December 2022 (7,391,988 “pre-Omicron” sequences and 6,830,473 “Omicron-present” sequences). CI, confidence interval.

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)