DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action

被引：6

作者：

Iaconis, Daniela ^{[1
]}

Caccuri, Francesca ^{[2
]}

Manelfi, Candida ^{[1
]}

Talarico, Carmine ^{[1
]}

Bugatti, Antonella ^{[2
]}

Filippini, Federica ^{[2
]}

Zani, Alberto ^{[2
]}

Novelli, Rubina ^{[3
]}

Kuzikov, Maria ^{[4
,5
]}

Ellinger, Bernhard ^{[4
,5
]}

Gribbon, Philip ^{[4
,5
]}

Riecken, Kristoffer ^{[6
]}

Esposito, Francesca ^{[7
]}

Corona, Angela ^{[7
]}

Tramontano, Enzo ^{[7
]}

Beccari, Andrea Rosario ^{[1
]}

Caruso, Arnaldo ^{[2
]}

Allegretti, Marcello ^{[3
]}

机构：

[1] Dompe Farmaceut SpA, EXSCALATE, Via Tommaso Amicis 95, I-80131 Naples, Italy

[2] Univ Brescia, Sect Microbiol, Dept Mol & Translat Med, I-25123 Brescia, Italy

[3] Dompe Famaceut SpA, Via Campo Pile Snc, I-67100 Laquila, Italy

[4] Fraunhofer Inst Translat Med & Pharmacol ITMP, Schnackenburgallee 114, D-22525 Hamburg, Germany

[5] Fraunhofer Cluster Excellence Immune Mediated Dis, Theodor Stern Kai 7, D-60596 Frankfurt, Germany

[6] Univ Med Ctr Hamburg Eppendorf, Res Dept Cell & Gene Therapy, Dept Stem Cell Transplantat, D-20246 Hamburg, Germany

[7] Univ Cagliari, Dept Life & Environm Sci, Cittadella Univ SS554, I-09042 Monserrato, CA, Italy

来源：

VIRUSES-BASEL | 2023年 / 15卷 / 05期

关键词：

COVID-19; drug repurposing; methotrexate; EXSCALATE; virtual screening; molecular docking; anti-viral activity; SARS-CoV-2; viral entry; nsp13; LOW-DOSE METHOTREXATE; ADENOSINE RELEASE; PRALATREXATE; TRIMETREXATE; COVID-19; EFFICACY; RECEPTOR; ANALOG;

D O I：

10.3390/v15051128

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.

引用

页数：16

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