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Antiviral Compounds Against SARS-COV-2

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Antiviral Compounds Against SARS-COV-2

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Antiviral Compounds Against SARS-COV-2

  1. 1. ANTIVIRAL COMPOUNDS AGAINST SARS-COV-2 December 9, 2021 Jingxin Wang, Ph.D. Assistant Professor University of Kansas, Lawrence
  2. 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. 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. 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. 5. Optimization of the CoV-2 RNA Ligand
  6. 6. C30: Target Validation
  7. 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. 8. Ribonuclease targeting chimera (RIBOTAC)
  9. 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. 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. 11. Questions?

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