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The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (11, 13, 14, 17, 20, 58, 60, 62, and 70) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC50 values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds 13, 62, and 70 exert their activities in the HAdV entry pathway, while compounds 14 and 60 likely target the HAdV DNA replication, and 11, 17, 20, and 58 inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections., This work was supported by the UTMB Technology Commercialization Program, John Sealy Memorial Endowment Fund, and Institute for Translational Sciences (ITS) at UTMB, the Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), cofinanced by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014-2020, the Carlos III Health Institute (DTS17/00130), and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT) grants. J.S.-C. is a researcher belonging to the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain.

Over the years, human adenovirus (HAdV) has progressively been recognized as a significant viral pathogen. Traditionally associated with self-limited respiratory, gastrointestinal, and conjunctival infections, mainly in immunocompromised patients, HAdV is currently considered to be a pathogen presenting significant morbidity and mortality in both immunosuppressed and otherwise healthy individuals. Currently available therapeutic options are limited because of their lack of effectivity and related side effects. In this context, there is an urgent need to develop effective anti-HAdV drugs with suitable therapeutic indexes. In this work, we identified new serinol-derived benzoic acid esters as novel scaffolds for the inhibition of HAdV infections. A set of 38 compounds were designed and synthesized, and their antiviral activity and cytotoxicity were evaluated. Four compounds (13, 14, 27, and 32) inhibited HAdV infection at low micromolar concentrations (2.82–5.35 μM). Their half maximal inhibitory concentration (IC50) values were lower compared to that of cidofovir, the current drug of choice. All compounds significantly reduced the HAdV DNA replication process, while they did not block any step of the viral entry. Our results showed that compounds 13, 14, and 32 seem to be targeting the expression of the E1A early gene. Moreover, all four derivatives demonstrated a significant inhibition of human cytomegalovirus (HCMV) DNA replication. This new scaffold may represent a potential tool useful for the development of effective anti-HAdV drugs., This work has been supported by Ministerio de Ciencia, Innovación y Universidades, Plan Estatal 2017-2020 Retos-Proyectos I+D+i (PID2019-104767RB-I00), Ministerio de Economı́a y Competitividad, Plan Estatal 2013-2016 Retos-Proyectos I + D + i (CTQ2016-78580-C2-2-R) and by Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), cofinanced by European Development Regional Fund “A way to achieve Europe”, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI17/01055; PI18/01191) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía. M.V.-H. also thanks Ministerio de Economı́a y Competitividad, Plan Estatal 2013-2016 Excelencia I+D+i (CTQ2016-78703-P).

Nowadays there is not an effective drug for the treatment of infections caused by human adenovirus (HAdV) which supposes a clinical challenge, especially for paediatric and immunosuppressed patients. Here, we describe the design, synthesis and biological evaluation as anti-adenovirus agents of a new library (57 compounds) of diester, monoester and triazole derivatives based on 3-amino-1,2-propanediol skeleton. Seven compounds (17, 20, 26, 34, 44, 60 and 66) were selected based on their high anti-HAdV activity at low micromolar concentration (IC50 from 2.47 to 5.75 µM) and low cytotoxicity (CC50 from 28.70 to >200 µM). In addition, our mechanistic assays revealed that compounds 20 and 44 might be targeting specifically the HAdV DNA replication process, and compound 66 would be targeting HAdV E1A mRNA transcription. For compounds 17, 20, 34 and 60, the mechanism of action seems to be associated with later steps after HAdV DNA replication., This work has been supported by Ministerio de Ciencia, Innovación y Universidades, Plan Estatal 2017-2020 Retos - Proyectos I + D + i (PID2019-104767RB-I00); Ministerio de Economía y Competitividad, Plan Nacional I + D + i 2013-2016, Retos-Proyectos (CTQ2016-78580-C2-2-R); Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), cofinanced by European Development Regional Fund “A way to achieve Europe”, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI17/01055; PI18/01191) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía.

The kinetics of the SARS-CoV-2 viral load in respiratory airways and other tissues is of great interest to understand the pathogenesis, course, and the management of COVID-19 patients. Therefore, we read with much interest the systematic literature review recently published in the Journal of Infection by Walsh et al.1, concluding that viral load in upper respiratory samples peaks around the time of symptoms onset or a few days thereafter, and becomes undetectable about two weeks after symptom onset; moreover, there is evidence of prolonged virus detection in stool samples, with unclear clinical significance. Information regarding the use of other samples to improve patients’ management is lacking or inconsistent.1, 2, 3 Thus, the risk factors for bloodstream infection and the clinical meaning of SARS-CoV-2 RNAemia detection has not yet been completely elucidated., Supported by Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI, RD16/0016/0001, RD16/0016/0005, RD16/0016/0007, RD16/0016/0009, RD16/0016/0010, R D16/0016/0013) cofinanced by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020. JSC and EC received grants from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación , Proyectos de Investigación sobre el SARS-CoV-2 y la enfermedad COVID-19 ( COV20/00580 ; COV20/00370 ). J.S.C. is a researcher belonging to the program “Nicolás Monardes” (C-0059–2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain.

An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC50 = 0.27 μM), significantly decreased cytotoxicity (CC50 = 156.8 μM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections., This work was supported by UTMB Technology Commercialization Program, John Sealy Memorial Endowment Fund, and Institute for Translational Sciences (ITS) at UTMB, Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 20142020, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI17/01055; PI18/01191) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía. J.Z. is also partially supported by John D. Stobo, M.D., Distinguished Chair Endowment Fund at UTMB. M.E.P.I. is a postdoctoral researcher belonging to the program “Nicolás Monardes” (C1-0038-2019), Servicio Andaluz de Salud, Junta de Andalucía, Spain.

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 to 5.1 μM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs., This work has been supported by Ministerio de Economía y Competitividad, Plan Estatal 2013–2016 Retos-Proyectos I + D + i (CTQ2016-78580-C2-2-R) and by Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) – co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020, the Instituto de Salud Carlos III(DTS17/00130) and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT) grants. MVH also thanks Ministerio de Economía y Competitividad, Plan Estatal 2013–2016 Excelencia I + D + i (CTQ2016-78703-P). JSC is a researcher belonging to the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain. FA thanks Dipartimento di Farmacia e Scienze della Salute e della Nutrizione-Dipartimento di Eccellenza MIUR L 232/2016". JAV thanks Junta de Andalucia (Contrato de Garantías Juveniles).

The repositioning of drugs already approved by regulatory agencies for other indications is an emerging alternative for the development of new antimicrobial therapies. The repositioning process involves lower risks and costs than the de novo development of novel antimicrobial drugs. Currently, infections by adenovirus show a steady increment with a high clinical impact in immunosuppressed and immunocompetent patients. The lack of a safe and efficacious drug to treat these infections supports the search for new antiviral drugs. Here we evaluated the anti-adenovirus activity of niclosanide, oxyclozanide, and rafoxanide, three salicylanilide anthelmintic drugs. Also, we carried out the cytotoxicity evaluation and partial characterization of the mechanism of action of these drugs. The salicylanilide anthelmintic drugs showed significant anti-adenovirus activity at low micromolar concentrations with little cytotoxicity. Moreover, our mechanistic assays suggest differences in the way the drugs exert anti-adenovirus activity. Niclosamide and rafoxanide target transport of the HAdV particle from the endosome to the nuclear envelope, whilst oxyclozanide specifically targets adenovirus immediately early gene E1A transcription. Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia., Supported by Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) – co-financed by “A way to achieve Europe” ERDF, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI15/00489) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT). J.S.C. is supported by the “Contract to Access to the Spanish System of Research and Innovation of the Program of R + D + i of the University of Seville” (USE-13901-D) grant.

Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI &gt, 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.

Human adenovirus (HAdV) infection has an important clinical impact in the immunosuppressed population and is associated with high morbidity and mortality rates. The lack of a specific, safe and effective antiviral treatment against HAdV makes necessary the search for new therapeutic options. The aim of this study was to evaluate the in vitro activity of ganciclovir (GCV) against HAdV in co-infection by human cytomegalovirus (HCMV) and HAdV in cellular cultures. Quantitative real-time polymerase chain reaction (qPCR) was used to measure HAdV and HCMV DNA replication efficiency in monocultures and in co-infection situations in the presence of both cidofovir (CDV) and GCV. The effects of GCV and CDV were also evaluated in a burst assay (used to measure the production of virus particles) for both viruses, alone and in combination. GCV decreased by 1-log the HAdV DNA replication efficiency in co-infection with HCMV compared with its activity in HAdV monoculture. The burst assay showed that the reductions in virus yield in the presence of GCV were higher for HCMV and co-infection than for HAdV in monoculture (145.2±35.5- vs. 116.4±27.3- vs. 23.0±10.0-fold, respectively, P, Supported by Plan Nacional de I+D+i 2013‐2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) - co‐financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014‐2020, the Carlos III Health Institute (PI15/00489; DTS17/00130; PI18/01191) and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT) grants.