Thread by @RajlabN

SARSCoV2 BA.2 #subvaraints carrying #MainProtease (#MPro) mutations associated with reduced #nirmatrelvir (#Paxlovid) activity

Top #NSP5 (MPro) mutations: H164N, G15S, T135I

Should investigate if these NSP5 mutations are also associated with Paxlovid rebound.

1/n

Mpro mutations associated with reduced nirmatrelvir activity (≥3-fold higher Ki values): G15S (4.4-fold), T135I (3.5-fold), S144A (91.9-fold), H164N (6.4-fold),
H172Y (233-fold), Q189K (65.4-fold), and D248E (3.7-fold).

fda.gov/media/155050/d…

2/n

Omicron-MPro-Pax-Tracker: (by sublineage, by state/division, by county/location):

3/n
public.tableau.com/app/profile/ra…

Most frequent BA.2* with NSP5 (MPro) mutations: BA.2.3
Most frequent BA.1*: BA.1.1

4/n

Additional BA.2* + NSP5 mutations (no experimental activity data available)

NSP5_T21I (0.19%)
NSP5_T24I (0.23%)
NSP5_K90R (0.71%)
NSP5_P108S (0.12%)
NSP5_P132H (99.94%)*
NSP5_P241L (0.10%)
NSP5_H246N (0.18%)

NSP5_P132H mutation is observed in almost all BA.2*

5/n

NSP5 (MPro) bound to paxlovid (PDB: 7VLQ)

Residues within 5 A from the ligand Paxlovid (PF07321332) are highlighted.

These are the residues to closely watch...

(Generated graphic using UCSF Chimera)

6/n

For Queries... since all omicrons carry NSP5_P132H..
search for nsp5_p132h + nsp5_g15s (or others from the list ⬆️) instead of nsp5_g15s alone.

Sequence count (containing nsp5_p132h, nsp5_g15s)
Omicron- 338 sequences
Alpha - 0
Beta -0
Gamma - 0
Delta - 0
Lambda - 0
C.36 - 1

Similarly,

Sequence count (containing nsp5_p132h, nsp5_h164n)
Omicron- 1963 sequences
Alpha - 0
Beta -0
Gamma - 0
Delta - 1
Lambda - 0
C.36 - 0

Sequence count (containing nsp5_p132h, nsp5_t135i)
Omicron- 152 sequences
Alpha - 0
Beta -0
Gamma - 0
Delta - 0
Lambda - 0
C.36 - 0

Sequence count -containing nsp5_p132h, nsp5_s144a
Omicron- 2 sequences
Alpha - 0
Beta -0
Gamma - 0
Delta - 0
Lambda - 0
C.36 - 0

Sequence count -containing nsp5_p132h, nsp5_h172y
Omicron- 2 sequences
Alpha - 0
Beta -0
Gamma - 0
Delta - 0
Lambda - 0
C.36 - 0

Sequence count -containing nsp5_p132h, nsp5_q189k
Omicron- 17 sequences
Alpha - 0
Beta -0
Gamma - 0
Delta - 1
Lambda - 0
C.36 - 0

Sequence count -containing nsp5_p132h, nsp5_d248e
Omicron- 14 sequences
Alpha - 0
Beta -0
Gamma - 0
Delta - 0
Lambda - 0
C.36 - 0