Essentiality of fatty acid synthase in the 2D to anchorage-independent growth transition in transforming cells

Upregulation of fatty acid synthase (FASN) is a common event in cancer, although its mechanistic and potential therapeutic roles are not completely understood. In this study, we establish a key role of FASN during transformation. FASN is required for eliciting the anaplerotic shift of the Krebs cycle observed in cancer cells. However, its main role is to consume acetyl-CoA, which unlocks isocitrate dehydrogenase (IDH)-dependent reductive carboxylation, producing the reductive power necessary to quench reactive oxygen species (ROS) originated during the switch from two-dimensional (2D) to three-dimensional (3D) growth (a necessary hallmark of cancer). Upregulation of FASN elicits the 2D-to-3D switch; however, FASN's synthetic product palmitate is dispensable for this process since cells satisfy their fatty acid requirements from the media. In vivo, genetic deletion or pharmacologic inhibition of FASN before oncogenic activation prevents tumor development and invasive growth. These results render FASN as a potential target for cancer prevention studies.M.Q.F. is a recipient of the following grants: FIS PI13/00430 and FIS PI16/00354 funded by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Regional Development Fund (ERDF) and AECC Scientific Foundation (Beca de Retorno 2010). R.C. is a recipient of the following grants: FIS PI11/00832 and FIS PI14/00726 funded by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Regional Development Fund (ERDF), II14/00009 and PIE15/00068 from the Ministerio de Sanidad, Spain. N.S.C. is a recipient of an NIH grant (5R35CA197532). O.Y.T. is a recipient of the grants BFU2014-57466 from the Ministerio de Economia y Competitividad (MINECO). J.P.B. is funded by MINECO (SAF2016-78114-R), Instituto de Salud Carlos III (RD12/0043/0021), Junta de Castilla y Leon (Escalera de Excelencia CLU-2017-03), Ayudas Equipos Investigacion Biomedicina 2017 Fundacion BBVA, and Fundacion Ramon Areces. This study was partially supported by the generous donations from Fundacion CRIS Contra el Cancer and AVON Spain. We thank Drs. Erwin Wagner and Nabil Djouder for their critical review of the paper.S

Kinase inhibitors as underexplored antiviral agents

73 p.-12 fig.-1 tab.-1 graph. abst.Viral infections are a major health problem; therefore, there is an urgent need for novel therapeutic strategies.Antivirals used to target proteins encoded by the viral genome usually enhance drug resistance generated by the virus. A potentialsolution may be drugs acting at host-based targets since viruses are dependent on numerous cellular proteins and phosphorylationevents that are crucial during their life cycle. Repurposing existing kinase inhibitors as antiviral agents would help in the cost andeffectiveness of the process, but this strategy usually does not provide much improvement, and specific medicinal chemistryprograms are needed in thefield. Anyway, extensive use of FDA-approved kinase inhibitors has been quite useful in deciphering therole of host kinases in viral infection. The present perspective aims to review the state of the art of kinase inhibitors that target viralinfections in different development stages.Funding from“la Caixa”Banking Foundation (LCF/PR/HR19/52160012), CSIC (202020E103 and 202080E293),and AEI (Grant PID2019-105600RB-I00) is acknowledged.E.C. holds a JAE Intro fellowship (JAEINT_20_01339) from CSIC.Peer reviewedpostprin

Host-Directed FDA-Approved Drugs with Antiviral Activity against SARS-CoV-2 Identified by Hierarchical In Silico/In Vitro Screening Methods

The unprecedent situation generated by the COVID-19 global emergency has prompted us to actively work to fight against this pandemic by searching for repurposable agents among FDA approved drugs to shed light into immediate opportunities for the treatment of COVID-19 patients. In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way. To this end a multi-target virtual screening approach focused on host-based targets related to viral entry, followed by the experimental evaluation of the antiviral activity of selected compounds, has been carried out. As a result, five different potentially repurposable drugs interfering with viral entry—cepharantine, clofazimine, metergoline, imatinib and efloxate—have been identifiedThis research was funded by CSIC (201980E024, 202020E103 and PIE-RD-COVID-19 ref. E202020E079), EVA (European Virus Archive; grant agreement No 871029), ANID (Agencia Nacional de Investigación y Desarrollo de Chile, grant No COVID0199), and CONICYT-PCI (Comisión Nacional de Investigación Científica y Tecnológica de Chile—Programa de Cooperación Internacional, grant No REDES190074). I.M. was funded by H2020-MSCA-ITN-2017 (grant no. 765912) and V.N. holds a pre-doctoral FPU grant (FPU16/04466)Peer reviewe

Host-directed FDA-approved drugs with antiviral activity against SARS-CoV-2 identified by hierarchical in silico/in vitro screening methods

The unprecedent situation generated by the COVID-19 global emergency has prompted scientists around the world to actively work to fight against this pandemic. In this sense, it is remarkable the number of drug repurposing efforts trying to shed light into the COVID-19 patients treatment. In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way. A successful combination of a multi-target virtual screening approach focused on host-based targets related to viral entry and experimental evaluation of the antiviral activity of selected compounds has been carried out. As a result, three different potentially repurposable drugs interfering with viral entry, cepharantine, imatinib and efloxate, have been identified.Funding from CSIC (201980E024, 202020E103 and PIE-RD-COVID-19 ref. E202020E079), EVA (European Virus Archive; grant agreement No 871029), FONDECYT grant Nº 11180604 and CONICYT-PCI grant Nº REDES190074 is acknowledged. Dr. R. Molenkamp (Erasmus University Medical Center, Rotterdam, Netherlands; participant of the EVA-GLOBAL project) is acknowledged for the SARS32 CoV-2 strain NL/2020 virus. Dr. F. L. (Inserm-Lyon) is acknowledged for the materials required to produce retroviral pseudotypesPeer reviewe