DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

Ravikumar Jimmidi; Srinivas Chamakuri; Shuo Lu; Melek Nihan Ucisik; Peng Jen Chen; Kurt M. Bohren; Seyed Arad Moghadasi; Leroy Versteeg; Christina Nnabuife; Jian Yuan Li; Xuan Qin; Ying Chu Chen; John C. Faver; Pranavanand Nyshadham; Kiran L. Sharma; Banumathi Sankaran; Allison Judge; Zhifeng Yu; Feng Li; Jeroen Pollet; Reuben S. Harris; Martin M. Matzuk; Timothy Palzkill; Damian W. Young

doi:10.1038/s42004-023-00961-y

DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

Ravikumar Jimmidi
, Srinivas Chamakuri
, Shuo Lu
, Melek Nihan Ucisik
, Peng Jen Chen
, Kurt M. Bohren
, Seyed Arad Moghadasi
, Leroy Versteeg
, Christina Nnabuife
, Jian Yuan Li
, Xuan Qin
, Ying Chu Chen
, John C. Faver
, Pranavanand Nyshadham
, Kiran L. Sharma
, Banumathi Sankaran
, Allison Judge
, Zhifeng Yu
, Feng Li
, Jeroen Pollet

Reuben S. Harris, Martin M. Matzuk, Timothy Palzkill, Damian W. Young

Department of Biochemistry & Structural Biology

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

16 Scopus citations

Abstract

The development of SARS-CoV-2 main protease (M^pro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate M^pro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of M^pro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M^pro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M^pro with low nanomolar K _i values. Furthermore, these compounds demonstrate efficacy against mutant forms of M^pro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

Original language	English (US)
Article number	164
Journal	Communications Chemistry
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s42004-023-00961-y
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
Environmental Chemistry
Biochemistry
Materials Chemistry

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Jimmidi, R., Chamakuri, S., Lu, S., Ucisik, M. N., Chen, P. J., Bohren, K. M., Moghadasi, S. A., Versteeg, L., Nnabuife, C., Li, J. Y., Qin, X., Chen, Y. C., Faver, J. C., Nyshadham, P., Sharma, K. L., Sankaran, B., Judge, A., Yu, Z., Li, F., ... Young, D. W. (2023). DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors. Communications Chemistry, 6(1), Article 164. https://doi.org/10.1038/s42004-023-00961-y

Jimmidi, R, Chamakuri, S, Lu, S, Ucisik, MN, Chen, PJ, Bohren, KM, Moghadasi, SA, Versteeg, L, Nnabuife, C, Li, JY, Qin, X, Chen, YC, Faver, JC, Nyshadham, P, Sharma, KL, Sankaran, B, Judge, A, Yu, Z, Li, F, Pollet, J, Harris, RS, Matzuk, MM, Palzkill, T & Young, DW 2023, 'DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors', Communications Chemistry, vol. 6, no. 1, 164. https://doi.org/10.1038/s42004-023-00961-y

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title = "DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors",

abstract = "The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar K i values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.",

author = "Ravikumar Jimmidi and Srinivas Chamakuri and Shuo Lu and Ucisik, \{Melek Nihan\} and Chen, \{Peng Jen\} and Bohren, \{Kurt M.\} and Moghadasi, \{Seyed Arad\} and Leroy Versteeg and Christina Nnabuife and Li, \{Jian Yuan\} and Xuan Qin and Chen, \{Ying Chu\} and Faver, \{John C.\} and Pranavanand Nyshadham and Sharma, \{Kiran L.\} and Banumathi Sankaran and Allison Judge and Zhifeng Yu and Feng Li and Jeroen Pollet and Harris, \{Reuben S.\} and Matzuk, \{Martin M.\} and Timothy Palzkill and Young, \{Damian W.\}",

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doi = "10.1038/s42004-023-00961-y",

language = "English (US)",

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AU - Jimmidi, Ravikumar

AU - Chamakuri, Srinivas

AU - Lu, Shuo

AU - Ucisik, Melek Nihan

AU - Chen, Peng Jen

AU - Bohren, Kurt M.

AU - Moghadasi, Seyed Arad

AU - Versteeg, Leroy

AU - Nnabuife, Christina

AU - Li, Jian Yuan

AU - Qin, Xuan

AU - Chen, Ying Chu

AU - Faver, John C.

AU - Nyshadham, Pranavanand

AU - Sharma, Kiran L.

AU - Sankaran, Banumathi

AU - Judge, Allison

AU - Yu, Zhifeng

AU - Li, Feng

AU - Pollet, Jeroen

AU - Harris, Reuben S.

AU - Matzuk, Martin M.

AU - Palzkill, Timothy

AU - Young, Damian W.

PY - 2023/12

Y1 - 2023/12

N2 - The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar K i values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

AB - The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar K i values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

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DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

Abstract

ASJC Scopus subject areas

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