Title of Poster or Presentation

Design and Synthesis of 2-aminocyclobutanone SARS-CoV-2 ligands as potential antivirals to treat COVID-19

Submission Type

Oral/Paper Presentation

Degree Type

PhD

Discipline

Sciences

Department

Chemistry

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Restricted

Abstract or Description

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for highly fatal and contagious COVID-19 caused a pandemic with destructive effects on the world economy and health systems in 213 countries. Currently, the scientific community is racing to develop vaccines and antiviral drugs against SARS-CoV-2 which is resistant to existing SARS and MERS drugs. Our computer-aided drug design (CADD) of cyclobutanone based ligands targets seven crucial enzymes of SARS-CoV-2 life cycle. N-functionalized α-aminocyclobutanones can act as peptidomimetics1, and as the carbonyl is electrophilic due to ring strain, they may offer either specific or broad-spectrum inhibitors of hydrolases and proteases via a covalently bound reversible hemiacetal adduct with active site nucleophiles such as the catalytic cysteine of proteases. α-Aminocyclobutanones could also provide potential inhibitors of metalloenzymes as a reversible hydrated cyclobutanone-enzyme adduct.2 We employed Schrödinger LLC, 2020-1 in virtual screening of 80 α-aminocyclobutanones analogs against seven target enzymes of SARS-CoV-2 and identified 11 N-tosyl amino acid cyclobutanone hit molecules against Helicase and 4 seed compounds against Papain-Like Proteinase (PLPro), 3-Chymotrypsin-Like Protease (3CLpro), and RNA-directed RNA polymerase (RdRp) with potential SARS-CoV-2 inhibition. Synthesis of a peptidomimetic cyclobutanone library including cyclobutanone hits was achieved via a modular 2-aminocyclobutanone synthon following our previously reported method.3 Progress in the synthesis of cyclobutanone Helicase hits and the in vitro testing will be presented.

  1. N. Armoush, P. Syal, D. P. Becker Synth. Commun. 2008, 38, 1679 –1687.
  2. M. I. Abboud, M. Kosmopoulou, A. Krismanich, J. W. Johnson, P. Hinchliffe, J. Brem, T. D. Claridge, J. Spencer, C. Schofield, G. I. Dmitrienko Chem. A Eur. J. 2017, 24, 5734–5737.
  3. T. S. Habeeb Mohammad, C. T. Reidl, M. Zeller, D. P. Becker Tet. Lett, 2020, 61 151632.

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Design and Synthesis of 2-aminocyclobutanone SARS-CoV-2 ligands as potential antivirals to treat COVID-19

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for highly fatal and contagious COVID-19 caused a pandemic with destructive effects on the world economy and health systems in 213 countries. Currently, the scientific community is racing to develop vaccines and antiviral drugs against SARS-CoV-2 which is resistant to existing SARS and MERS drugs. Our computer-aided drug design (CADD) of cyclobutanone based ligands targets seven crucial enzymes of SARS-CoV-2 life cycle. N-functionalized α-aminocyclobutanones can act as peptidomimetics1, and as the carbonyl is electrophilic due to ring strain, they may offer either specific or broad-spectrum inhibitors of hydrolases and proteases via a covalently bound reversible hemiacetal adduct with active site nucleophiles such as the catalytic cysteine of proteases. α-Aminocyclobutanones could also provide potential inhibitors of metalloenzymes as a reversible hydrated cyclobutanone-enzyme adduct.2 We employed Schrödinger LLC, 2020-1 in virtual screening of 80 α-aminocyclobutanones analogs against seven target enzymes of SARS-CoV-2 and identified 11 N-tosyl amino acid cyclobutanone hit molecules against Helicase and 4 seed compounds against Papain-Like Proteinase (PLPro), 3-Chymotrypsin-Like Protease (3CLpro), and RNA-directed RNA polymerase (RdRp) with potential SARS-CoV-2 inhibition. Synthesis of a peptidomimetic cyclobutanone library including cyclobutanone hits was achieved via a modular 2-aminocyclobutanone synthon following our previously reported method.3 Progress in the synthesis of cyclobutanone Helicase hits and the in vitro testing will be presented.

  1. N. Armoush, P. Syal, D. P. Becker Synth. Commun. 2008, 38, 1679 –1687.
  2. M. I. Abboud, M. Kosmopoulou, A. Krismanich, J. W. Johnson, P. Hinchliffe, J. Brem, T. D. Claridge, J. Spencer, C. Schofield, G. I. Dmitrienko Chem. A Eur. J. 2017, 24, 5734–5737.
  3. T. S. Habeeb Mohammad, C. T. Reidl, M. Zeller, D. P. Becker Tet. Lett, 2020, 61 151632.