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

Thahani S. Habeeb Mohammad; Cory T. Reidl; Yash Gupta; Dawid Maciorowski; Prakasha Kempaiah; Daniel P. Becker

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

Thahani S. Habeeb Mohammad, Cory T. Reidl, Yash Gupta, Dawid Maciorowski, Prakasha Kempaiah, Daniel P. Becker

Department of Chemistry and Biochemistry

Research output: Contribution to journal › Article › peer-review

Abstract

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 peptidomimetics 1 , 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. <ol> <li> N. Armoush, P. Syal, D. P. Becker Synth. Commun . 2008 , 38 , 1679 –1687. </li> <li> 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. </li> <li> T. S. Habeeb Mohammad, C. T. Reidl, M. Zeller, D. P. Becker Tet. Lett, 2020, 61 151632. </li> </ol>

Original language	American English
Journal	Graduate Research Symposium
State	Published - Jun 6 2020

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

abstract = " 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 peptidomimetics 1 , 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. N. Armoush, P. Syal, D. P. Becker Synth. Commun . 2008 , 38 , 1679 –1687. 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. T. S. Habeeb Mohammad, C. T. Reidl, M. Zeller, D. P. Becker Tet. Lett, 2020, 61 151632. ",

author = "{Habeeb Mohammad}, {Thahani S.} and Reidl, {Cory T.} and Yash Gupta and Dawid Maciorowski and Prakasha Kempaiah and Becker, {Daniel P.}",

year = "2020",

month = jun,

day = "6",

language = "American English",

journal = "Graduate Research Symposium",

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T1 - Design and Synthesis of 2-aminocyclobutanone SARS-CoV-2 ligands as potential antivirals to treat COVID-19

AU - Habeeb Mohammad, Thahani S.

AU - Reidl, Cory T.

AU - Gupta, Yash

AU - Maciorowski, Dawid

AU - Kempaiah, Prakasha

AU - Becker, Daniel P.

PY - 2020/6/6

Y1 - 2020/6/6

N2 - 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 peptidomimetics 1 , 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. N. Armoush, P. Syal, D. P. Becker Synth. Commun . 2008 , 38 , 1679 –1687. 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. T. S. Habeeb Mohammad, C. T. Reidl, M. Zeller, D. P. Becker Tet. Lett, 2020, 61 151632.

AB - 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 peptidomimetics 1 , 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. N. Armoush, P. Syal, D. P. Becker Synth. Commun . 2008 , 38 , 1679 –1687. 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. T. S. Habeeb Mohammad, C. T. Reidl, M. Zeller, D. P. Becker Tet. Lett, 2020, 61 151632.

UR - https://ecommons.luc.edu/grs/2020/oralpaperpresentations/10

M3 - Article

JO - Graduate Research Symposium

JF - Graduate Research Symposium

ER -

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

Abstract

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