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1. ANTIVIRAL COMPOUNDS AGAINST
SARS-COV-2
December 9, 2021
Jingxin Wang, Ph.D.
Assistant Professor
University of Kansas, Lawrence

2. Introduction: Where to target in CoV-2 life cycle?
Neutralizing antibodies
e.g., bamlanivimab
ACE2
TMPRSS2
Cytoplasm
Coronavirus
① Binding and viral entry via
membrane fusion or endocytosis
1. Antisense oligonucleotides
2. RNA-targeting small molecules
Ribosome
RNA genome
(+sense)
② Translation
of polypeptide
③ Autoproteolysis
Protease inhibitors
e.g., Paxlovoid, MPI8, bepridil
Non-structural
proteins (nsps)
Replication transcription
Complex (RTC)
pp1a
pp1ab
④ RTC formation and
(–sense) genomic RNA
replication
⑤ (+sense) genomic
and sub-genomic RNA
transcription/replication
RTC inhibitor
e.g., remdesivir,
molnupiravir
(+) Genomic RNA
(+) Sub-genomic RNA
S
N
M
E
N
Nucleocapsid
⑥ Translation of sub-
genomic mRNA into
structural proteins and
accessory proteins
⑦ Nucleocapsid buds
into ERGIC studded with
S, E, M proteins
ERGIC
⑧ Formation of virion
⑨ Exocytosis
Exocytic
vesicle
Endoplasmic
reticulum (ER)
Hegde, S., Tang, Z., Zhao, J., Wang, J.*
(2021) Inhibition of SARS-CoV-2 by
targeting conserved viral RNA structures
and sequences. Front. Chem. In Press.
DOI: 10.3389/fchem.2021.802766
Pros:
1. New mechanism
2. Avoid drug resistance
3. Synergistic effect
Cons:
1. Gene selectivity
2. Organ distribution

3. Introduction: RNA-targeting chimeras
Traditional RNA-binding antisense development
RNA-degrading small-molecule chimeras
Zhao J,..., Wang J*. The RNA Architecture of the SARS-CoV-2 3'-Untranslated Region. Viruses.
2020;12(12):1473. doi:10.3390/v12121473

4. Coumarin derivative: a versatile RNA binder
 Recognize a variety of RNA structures
 Rings A and DE controls the binding affinity
and specificity
Tang Z, ... Wang J*. Nucleic Acids Res. 2021;49(14):7870. doi:10.1093/nar/gkab602

5. Optimization of the CoV-2 RNA Ligand

6. C30: Target Validation

7. Effector: RNA Degradation Recruiter
Literature on RNase L recruiter: Haniff HS, ..., Disney MD*. ACS Cent Sci. 2020;6(10):1713-1721.
doi:10.1021/acscentsci.0c00984

8. Ribonuclease targeting chimera (RIBOTAC)

9. Summary
RNA-degrading chimeras: novel antiviral modalities
 Analogy of PROTAC in RNAs
Completely different mechanism to all existing drug
development pipelines
 Potential cocktail therapies
Adaptable to combat any RNA viruses
Seeking sponsored research funds and/or licensees for
commercialization

10. Aswini K. Betha, PhD, CLP
KU Center for Technology Commercialization (KUCTC)
The University of Kansas
Phone: (785) 864-1775
Email: abetha@ku.edu
www.kuctc.ku.edu
Jim Baxendale
James G. Baxendale
Consultant, Whiteboard2Boardroom
A bi-state initiative
UMKC Innovation Center
(c) (816)-679-7798
Baxendalej@umkc.edu
http://www.whiteboard2boardroom.com
Contact:

11. Questions?