Whiteboard2Boardroom collaborates with more than 21 research institutions, hospitals and corporation to move technologies out of research labs into the marketplace.
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
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
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: