Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2

Miguel M. Vaidergorn; Aline D. Purificação; Pedro I.P. Leite; Sabrina Silva-Mendonça; Wemenes J.L. Silva; Thiago dos Santos; Daniel Gedder Silva; Bruna Fleck Godoi; Carolina Q. Sacramento; Mayara Mattos; Natalia Fintelman-Rodrigues; Caroline S. Freitas; Luis Eduardo Alves Damasceno; Yoko Shishikura; Alex Brown; Karolina Wrobel; Jennifer Riley; Thiago M.L. Souza; Kevin D. Read; José C. Alves-Filho; Carolina H. Andrade; M. Cristina Nonato; Flavio S. Emery

doi:10.1016/j.ejmech.2025.117876

Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2

Miguel M. Vaidergorn, Aline D. Purificação, Pedro I.P. Leite, Sabrina Silva-Mendonça, Wemenes J.L. Silva, Thiago dos Santos, Daniel Gedder Silva, Bruna Fleck Godoi, Carolina Q. Sacramento, Mayara Mattos, Natalia Fintelman-Rodrigues, Caroline S. Freitas, Luis Eduardo Alves Damasceno, Yoko Shishikura, Alex Brown, Karolina Wrobel, Jennifer Riley, Thiago M.L. Souza, Kevin D. Read, José C. Alves-FilhoCarolina H. Andrade (Lead / Corresponding author), M. Cristina Nonato (Lead / Corresponding author), Flavio S. Emery (Lead / Corresponding author)

Drug Discovery Unit

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

Abstract

In response to the rising challenge of pathogen resistance to anti-infective therapies, innovative approaches such as host-directed therapy are being investigated to bypass these resistance mechanisms. Dihydroorotate dehydrogenase (DHODH) is a crucial enzyme for synthesizing pyrimidines, which are essential for RNA and DNA biosynthesis. Inhibiting DHODH can deplete the nucleotide pool, thereby impairing the replication of pathogens that depend on this pathway. In this study, we evaluated a library of fragment-like compounds against human DHODH (HsDHODH) and identified a 1,2-diarylethine scaffold as a potential new inhibitor. Utilizing the predicted binding mode and the activity of fragments 3a and 3l against HsDHODH, we designed and synthesized 14 novel diarylethine derivatives focused on improving their potency against the enzyme. The activity of the most potent compound (3e, IC₅₀ 1.50 ± 0.02 μM) was translated to antiviral activity against SARS-CoV-2 in infected Calu-3 cells (EC₅₀ 1.7 ± 0.5 μM), with low cytotoxicity. Early ADME in vitro evaluation indicated a need for improved solubility, which will be addressed in subsequent multi-parameter optimization efforts. These findings pave the way for developing novel HsDHODH inhibitors with enhanced pharmacological and pharmacokinetics profiles, offering a promising strategy to address viral diseases that are resistant to conventional treatments.

Original language	English
Article number	117876
Number of pages	17
Journal	European Journal of Medicinal Chemistry
Volume	297
Early online date	21 Jun 2025
DOIs	https://doi.org/10.1016/j.ejmech.2025.117876
Publication status	Published - 5 Nov 2025

Keywords

Antiviral activity
Diarylethines
Dihydroorotate dehydrogenase
Fragment-based drug discovery
Host-directed therapy
Human DHODH inhibitor
Structure-based drug discovery

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2025.117876

Author Accepted ManuscriptAccepted author manuscript, 2.4 MBLicence: CC BY

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Vaidergorn, M. M., Purificação, A. D., Leite, P. I. P., Silva-Mendonça, S., Silva, W. J. L., Santos, T. D., Silva, D. G., Godoi, B. F., Sacramento, C. Q., Mattos, M., Fintelman-Rodrigues, N., Freitas, C. S., Damasceno, L. E. A., Shishikura, Y., Brown, A., Wrobel, K., Riley, J., Souza, T. M. L., Read, K. D., ... Emery, F. S. (2025). Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2. European Journal of Medicinal Chemistry, 297, Article 117876. https://doi.org/10.1016/j.ejmech.2025.117876

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title = "Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2",

abstract = "In response to the rising challenge of pathogen resistance to anti-infective therapies, innovative approaches such as host-directed therapy are being investigated to bypass these resistance mechanisms. Dihydroorotate dehydrogenase (DHODH) is a crucial enzyme for synthesizing pyrimidines, which are essential for RNA and DNA biosynthesis. Inhibiting DHODH can deplete the nucleotide pool, thereby impairing the replication of pathogens that depend on this pathway. In this study, we evaluated a library of fragment-like compounds against human DHODH (HsDHODH) and identified a 1,2-diarylethine scaffold as a potential new inhibitor. Utilizing the predicted binding mode and the activity of fragments 3a and 3l against HsDHODH, we designed and synthesized 14 novel diarylethine derivatives focused on improving their potency against the enzyme. The activity of the most potent compound (3e, IC50 1.50 ± 0.02 μM) was translated to antiviral activity against SARS-CoV-2 in infected Calu-3 cells (EC50 1.7 ± 0.5 μM), with low cytotoxicity. Early ADME in vitro evaluation indicated a need for improved solubility, which will be addressed in subsequent multi-parameter optimization efforts. These findings pave the way for developing novel HsDHODH inhibitors with enhanced pharmacological and pharmacokinetics profiles, offering a promising strategy to address viral diseases that are resistant to conventional treatments.",

keywords = "Antiviral activity, Diarylethines, Dihydroorotate dehydrogenase, Fragment-based drug discovery, Host-directed therapy, Human DHODH inhibitor, Structure-based drug discovery",

author = "Vaidergorn, \{Miguel M.\} and Purifica{\c c}{\~a}o, \{Aline D.\} and Leite, \{Pedro I.P.\} and Sabrina Silva-Mendon{\c c}a and Silva, \{Wemenes J.L.\} and Santos, \{Thiago dos\} and Silva, \{Daniel Gedder\} and Godoi, \{Bruna Fleck\} and Sacramento, \{Carolina Q.\} and Mayara Mattos and Natalia Fintelman-Rodrigues and Freitas, \{Caroline S.\} and Damasceno, \{Luis Eduardo Alves\} and Yoko Shishikura and Alex Brown and Karolina Wrobel and Jennifer Riley and Souza, \{Thiago M.L.\} and Read, \{Kevin D.\} and Alves-Filho, \{Jos{\'e} C.\} and Andrade, \{Carolina H.\} and Nonato, \{M. Cristina\} and Emery, \{Flavio S.\}",

note = "Publisher Copyright: {\textcopyright} 2025 Elsevier Masson SAS",

year = "2025",

month = nov,

day = "5",

doi = "10.1016/j.ejmech.2025.117876",

language = "English",

volume = "297",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier",

}

Vaidergorn, MM, Purificação, AD, Leite, PIP, Silva-Mendonça, S, Silva, WJL, Santos, TD, Silva, DG, Godoi, BF, Sacramento, CQ, Mattos, M, Fintelman-Rodrigues, N, Freitas, CS, Damasceno, LEA, Shishikura, Y , Brown, A, Wrobel, K, Riley, J, Souza, TML, Read, KD, Alves-Filho, JC, Andrade, CH, Nonato, MC & Emery, FS 2025, 'Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2', European Journal of Medicinal Chemistry, vol. 297, 117876. https://doi.org/10.1016/j.ejmech.2025.117876

Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2. / Vaidergorn, Miguel M.; Purificação, Aline D.; Leite, Pedro I.P. et al.
In: European Journal of Medicinal Chemistry, Vol. 297, 117876, 05.11.2025.

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

TY - JOUR

T1 - Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy

T2 - Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2

AU - Vaidergorn, Miguel M.

AU - Purificação, Aline D.

AU - Leite, Pedro I.P.

AU - Silva-Mendonça, Sabrina

AU - Silva, Wemenes J.L.

AU - Santos, Thiago dos

AU - Silva, Daniel Gedder

AU - Godoi, Bruna Fleck

AU - Sacramento, Carolina Q.

AU - Mattos, Mayara

AU - Fintelman-Rodrigues, Natalia

AU - Freitas, Caroline S.

AU - Damasceno, Luis Eduardo Alves

AU - Shishikura, Yoko

AU - Brown, Alex

AU - Wrobel, Karolina

AU - Riley, Jennifer

AU - Souza, Thiago M.L.

AU - Read, Kevin D.

AU - Alves-Filho, José C.

AU - Andrade, Carolina H.

AU - Nonato, M. Cristina

AU - Emery, Flavio S.

PY - 2025/11/5

Y1 - 2025/11/5

N2 - In response to the rising challenge of pathogen resistance to anti-infective therapies, innovative approaches such as host-directed therapy are being investigated to bypass these resistance mechanisms. Dihydroorotate dehydrogenase (DHODH) is a crucial enzyme for synthesizing pyrimidines, which are essential for RNA and DNA biosynthesis. Inhibiting DHODH can deplete the nucleotide pool, thereby impairing the replication of pathogens that depend on this pathway. In this study, we evaluated a library of fragment-like compounds against human DHODH (HsDHODH) and identified a 1,2-diarylethine scaffold as a potential new inhibitor. Utilizing the predicted binding mode and the activity of fragments 3a and 3l against HsDHODH, we designed and synthesized 14 novel diarylethine derivatives focused on improving their potency against the enzyme. The activity of the most potent compound (3e, IC50 1.50 ± 0.02 μM) was translated to antiviral activity against SARS-CoV-2 in infected Calu-3 cells (EC50 1.7 ± 0.5 μM), with low cytotoxicity. Early ADME in vitro evaluation indicated a need for improved solubility, which will be addressed in subsequent multi-parameter optimization efforts. These findings pave the way for developing novel HsDHODH inhibitors with enhanced pharmacological and pharmacokinetics profiles, offering a promising strategy to address viral diseases that are resistant to conventional treatments.

AB - In response to the rising challenge of pathogen resistance to anti-infective therapies, innovative approaches such as host-directed therapy are being investigated to bypass these resistance mechanisms. Dihydroorotate dehydrogenase (DHODH) is a crucial enzyme for synthesizing pyrimidines, which are essential for RNA and DNA biosynthesis. Inhibiting DHODH can deplete the nucleotide pool, thereby impairing the replication of pathogens that depend on this pathway. In this study, we evaluated a library of fragment-like compounds against human DHODH (HsDHODH) and identified a 1,2-diarylethine scaffold as a potential new inhibitor. Utilizing the predicted binding mode and the activity of fragments 3a and 3l against HsDHODH, we designed and synthesized 14 novel diarylethine derivatives focused on improving their potency against the enzyme. The activity of the most potent compound (3e, IC50 1.50 ± 0.02 μM) was translated to antiviral activity against SARS-CoV-2 in infected Calu-3 cells (EC50 1.7 ± 0.5 μM), with low cytotoxicity. Early ADME in vitro evaluation indicated a need for improved solubility, which will be addressed in subsequent multi-parameter optimization efforts. These findings pave the way for developing novel HsDHODH inhibitors with enhanced pharmacological and pharmacokinetics profiles, offering a promising strategy to address viral diseases that are resistant to conventional treatments.

KW - Antiviral activity

KW - Diarylethines

KW - Dihydroorotate dehydrogenase

KW - Fragment-based drug discovery

KW - Host-directed therapy

KW - Human DHODH inhibitor

KW - Structure-based drug discovery

UR - https://www.scopus.com/pages/publications/105009351507

U2 - 10.1016/j.ejmech.2025.117876

DO - 10.1016/j.ejmech.2025.117876

M3 - Article

C2 - 40592187

AN - SCOPUS:105009351507

SN - 0223-5234

VL - 297

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 117876

ER -

Targeting dihydroorotate dehydrogenase (DHODH) for host-directed therapy: Discovery of a novel alkyne-based scaffold inhibitor effective against SARS-CoV-2

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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