drugs

actually, those 95 authors did provide a table of the drugs they’ve tested which show promise against coronavirus. Here it is. I fear the structure of the table has not survived the paste. I refer the interested reader back to the URL in my last blog post. Take it as a demonstration of the amazing array of stuff out that that may be able to corral our annoying little visitor.

Table 1a. Literature-deriveda drugs and reagents that modulate SARS-Cov-2 interactors.

Compound Name

Compound Structure

Human Gene

Viral Bait              Drug Status

Activity (nM)

Silmitasertib106,107

CSNK2A2             N

Approved (Cancer)

CK2 inhibitor IC50 = 1

TMCB108                                                           CSNK2A2            N

Pre-clinical

Multi-targeted protein kinase inhibitor

Ki  = 21

Apicidin109                                                            HDAC2            Nsp5             Pre-clinical            HDAC inhibitor IC50 = 120

Valproic Acid110,111                                                      HDAC2            Nsp5

Approved (CNS

diseases, Cancer)

HDAC2 inhibitor Ki = 5

Bafilomycin A1112                                                     ATP6AP1          Nsp6             Pre-clinical           ATPase inhibitor IC50 = 100

E-52862113                                                          SIGMAR1          Nsp6            Clinical Trial        Sigma 1 antagonist IC50 = 17

PD-144418114                                                       SIGMAR1          Nsp6             Pre-clinical         Sigma 1 antagonist Ki = 0.8

RS-PPCC115                                                        SIGMAR1          Nsp6             Pre-clinical           Sigma 1 agonist Ki = 1.5

PB28

SIGMAR1

116                                                                                           TMEM97

Nsp6             Pre-clinical Orf9c

Sigma 1/2 modulator IC50 = 15

117                                                                                   SIGMAR1

Nsp6

Approved

Sigma 1/2 modulator

Haloperidol

TMEM97

Orf9c

(CNS

diseases)

Ki = 2-12

Entacapone

118,119

COMT             Nsp7

Approved (Parkinson’s disease)

COMT inhibitor IC50 = 151

Indomethacin120                                                       PTGES2           Nsp7

Approved (Inflammation, Pain)

Prostaglandin E2 synthase inhibitor IC50 = 750

Metformin121                                                          NDUFs            Nsp7

Orf9c

Approved (Diabetes)

MRC 1 inhibitor (indirect)

Ponatinib122                                                            RIPK1           Nsp12             Approved (Cancer)

RIPK1 inhibitor IC50 = 12

H-89123                                                             PRKACA         Nsp13            Pre-clinical

Protein kinase A inhibitor

KD  = 48

Merimepodib124                                                       IMPDH2          Nsp14           Clinical Trial           IMPDH inhibitor Ki = 10

Migalastat

125

α-Gal inhibitor IC50 = 40

Mycophenolic acid

126

IMPDH inhibitor IC50 = 20

  GLA   Nsp14 Approved (Fabry     disease)   IMPDH2   Nsp14 Approved (Organ     rejection)    

Ribavirin127                                                           IMPDH2          Nsp14             Approved (Viral infection)

IMPDH inhibitor IC50 = 100-250

XL413128                                                             DNMT1            Orf8             Clinical Trial            CDC7 inhibitor IC50 = 3.4

CCT 365623129                                                           LOX               Orf8

Pre-clinical

LOXL2 inhibitor IC50 = 1500

Midostaurin130                                                       MARK2/3          Orf9b              Approved (Cancer)

Protein kinase inhibitor MARK1

KD = 100 MARK3 KD = 23

Ruxolitinib

131

MARK2/3          Orf9b

Approved (Myelofibrosis)

Protein kinase inhibitor MARK1

KD = 660 MARK3

KD > 10000

ZINC1775962367132                                                   DCTPP1          Orf9b             Pre-clinical

ZINC4326719133                                                      DCTPP1          Orf9b             Pre-clinical

ZINC4511851134                                                      DCTPP1          Orf9b             Pre-clinical

dCTPase inhibitor IC50 = 47

DCTPP1 inhibitor IC50 = 19

dCTPase inhibitor IC50 = 20

ZINC95559591

135                                                                                 MARK3

TBK1

Orf9b            Pre-clinical Nsp13

Protein kinase inhibitor MARK3 IC50 = 12

TBK1 IC50 = 6

AC-55541136                                                           F2RL1            Orf9c             Pre-clinical

AZ8838137                                                             F2RL1            Orf9c             Pre-clinical

PAR agonist pEC50 = 6.7

PAR antagonist IC50 = 344

Daunorubicin

138

ABCC1           Orf9c

Approved (Cancer)

Topoisomerase inhibitor

Ki  = 70

GB110139                                                              F2RL1            Orf9c             Pre-clinical              PAR2 agonist EC50 = 280

S-verapamil140

ABCC1           Orf9c

Approved (Hypertension)

Ca2+ channel inhibitor and drug efflux transporter inhibitor

Ki = 113

AZ3451137                                                             F2RL1            Orf9c             Pre-clinical

PAR2 negative allosteric modulator pKD = 15

  1. These drug-target associations are drawn from chemoinformatic searches of the literature, drawing on databases such as ChEMBL141, ZINC142 and IUPHAR/BPS Guide to Pharmacology143

Table 1b. Expert-identifieda drugs and reagents that modulate SARS-CoV-2 interactors.

Compound Name

Compound Structure

Human Gene/ Process

Viral Bait

Drug Status

Activity (nM)

ABBV-74468                                                                                                           BRD2/4                E          Clinical Trial

  Degrades BRD BRD2/4 E Pre-clinical proteins       IC50 <       10000    

dBET6144

BRD

inhibitor KD = 2.1

MZ1145                                                                                                                 BRD2/4                E           Pre-clinical

  BRD2/4 inhibitor BRD2 BRD2/4 E Clinical Trial IC50 = 25       BRD4       IC50 = 18    

CPI-0610146

Degrades BRD

proteins KD = 120-

228

Sapanisertib87,147                                                                                                       LARP1                N          Clinical Trial

mTOR

inhibitor IC50 = 1

Rapamycin87,148

LARP1 FKBP15 FKBP7/10

N

Nsp2 Orf8

Approved (Organ rejection)

mTOR

inhibitor (with FKBP) IC50 = 2.0

149                                                                                                           EIF4E2/H            Nsp2        Clinical Trial          EIF4a

Zotatifin

inhibitor IC50 = 1.5

Verdinexor

NUPs

150                                                                                                            RAE1

Nsp4 Nsp9 Orf6

Clinical Trial

XPO1

nuclear export inhibitor IC50 = 960

Chloroquine151                                                                                                      SIGMAR1           Nsp6

Approved (Malaria)

Sigma 1 binder Ki = 100

Dabrafenib152                                                                                                            NEK9               Nsp9          Approved (Cancer)

NEK9

inhibitor IC50 = 1

 CEP250 inhibitor
(with
WDB002CEP250Nsp13Clinical TrialFKBP)
    Kd = 0.29
      PPIA-
    IMPDH2
    modulator
Sanglifehrin A153IMPDH2Nsp14Pre-clinicalPPIA KD =
    0.2
    IDPDH2
    Binding

EC50 =

11.5 (with PPIA)

FK-506

154                                                                                                              FKBP7              Orf8

FKBP10

Approved (Organ rejection)

FKBP

binder

Pevonedistat67                                                                                                           CUL2              Orf10       Clinical Trial

Ternatin 4155                                                                                                       Translation                           Pre-clinical

NEDD8-

activating enzyme inhibitor IC50 = 4.7

eEF1A

inhibitor IC50 = 71

4E2RCat

58                                                                                                         Translation                           Pre-clinical

eIF4E/G PPI

inhibitor IC50 = 13500

Tomivosertib156,157                                                                                                 Translation                          Clinical Trial

MNK1/2

inhibitor IC50 = 2.4

Viral

158

Pre-clinical

Cyclophilin inhibitor

Compound 2

Transcription

KD = 24

Compound 10159                                                                                                          Viral

Transcription

PS306130                                                                                                           ER protein

processing

Pre-clinical

Pre-clinical

PI4K-IIIβ

inhibitor IC50 = 3.4

Sec61 inhibitor IC50 = 20-

500

IHVR-19029160,161

ER protein                          Clinical Trial processing

Antiviral activity

IC50 = 1200

Captopril

162

Cell Entry

Approved (Hypertension)

ACE

inhibitor Ki = 3

Lisinopril163

Cell Entry

Approved (Hypertension)

ACE

inhibitor Ki = 0.27

Camostat164,165                                                                                                      Cell Entry                             Approved (Pancreatitis)

Nafamostat164,166                                                                                                    Cell Entry                             Approved (Anticoagulant)

Serine protease 1 inhibitor IC50 < 1000

Serine protease 1 inhibitor IC50 = 100

Chloram-

phenicol167                                                                                                       Mitochondrial

ribosome

Approved (Bacterial infection)

Mito- chondrial ribosome inhibitor IC50 = 7400

Tigecycline168                                                                                                    Mitochondrial

ribosome

Approved (Bacterial infection)

Mito- chondrial ribosome inhibitor IC50 = 3300

Linezolid169

Mitochondrial ribosome

Approved (Bacterial infection)

Mito- chondrial ribosome inhibitor IC50 = 16000

a. These molecules derive from expert analysis of human protein interactors of SARS-Co-V2 and reagents and drugs that modulate them; not readily available from the chemoinformatically-searchable literature.

Published by rike52

I retired from the Rheumatology division of Michigan Medicine end of June '19 after 36 years there. Upon hitting Ann Arbor for the second time (I went to school here) it took me almost 8 months to meet Kathy, 17 months to buy her a house (on Harbal, where we still live), and 37 months to marry her. Kids never came, but we've been blessed with a crowd of colleagues, friends, neighbors and family that continues to grow. Lots of them are going to show up in this log eventually. Stay tuned.

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