Description of the research
The development of drugs to combat most viral infections is still at an early stage. Nevertheless, herpesviruses, HIV, and hepatitis B and C virus exemplify how years of research and detailed knowledge of viral replication cycles and protein functions can lead to important breakthroughs. The development and clinical application of antiviral drugs is a lengthy process, requiring multidisciplinary collaboration. To start, basic virological research should identify suitable viral or host targets. Cell-culture based assays can be used to identify hits and establish a mechanism of action. Our research, and that of our partners in several European projects, aims to identify antiviral drugs for emerging and neglected +RNA viruses, which is particularly challenging given their high mutation rate and ability to escape antiviral therapy. Currently, we are targeting the SARS- and MERS-coronaviruses, alphaviruses (chikungunya virus), and the flavivirus Zika virus. We have developed an extensive molecular biological toolbox for these pathogens, which all need to be handled at Biosafety level 3. This allows us to dissect their replicative cycle and mechanisms of inhibition in detail.
- Development of models and assays for (high-throughput) antiviral screening
- Identification of inhibitors of viral replication
- Exploring novel antiviral strategies targeting host factors
- Mechanism of action studies on newly identified antiviral drugs
- Small molecule inhibitors of Chikungunya virus: mechanisms of action and antiviral drug resistance. Kristina Kovacikova, Martijn J van Hemert. Online 14 September 2020 Antimicrob. Agents Chemother.DOI: 10.1128/AAC.01788-20
- Novel Class of Chikungunya Virus Small Molecule Inhibitors That Targets the Viral Capping Machinery. Abdelnabi R, Kovacikova K, Moesslacher J, Donckers K, Battisti V, Leyssen P, Langer T, Puerstinger G, Quérat G, Li C, Decroly E, Tas A, Marchand A, Chaltin P, Coutard B, van Hemert M, Neyts J, Delang L. Antimicrob Agents Chemother. 2020 Jun 23;64(7). DOI: 10.1099/acmi.imav2019.po0012
- Coronaviruses and arteriviruses display striking differences in their cyclophilin A-dependence during replication in cell culture. de Wilde AH, Zevenhoven-Dobbe JC, Beugeling C, Chatterji U, de Jong D, Gallay P, Szuhai K, Posthuma CC, Snijder EJ. Virology. 2018 Apr;517:148-156. doi: 10.1016/j.virol.2017.11.022.
- Bis(benzofuran-thiazolidinone)s and bis(benzofuran-thiazinanone)s as inhibiting agents for chikungunya virus. Hwu JR, Gupta NK, Tsay SC, Huang WC, Albulescu IC, Kovacikova K, van Hemert MJ. Antiviral Res. 2017 Oct;146:96-101.
- Suramin inhibits Zika virus replication by interfering with virus attachment and release of infectious particles. Albulescu IC, Kovacikova K, Tas A, Snijder EJ, van Hemert MJ. Antiviral Res. 2017 Jul;143:230-236.
- Alisporivir inhibits MERS- and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model. de Wilde AH, Falzarano D, Zevenhoven-Dobbe JC, Beugeling C, Fett C, Martellaro C, Posthuma CC, Feldmann H, Perlman S, Snijder EJ. Virus Res. 2017 Jan 15;228:7-13.
- Suramin inhibits chikungunya virus replication through multiple mechanisms. Albulescu IC, van Hoolwerff M, Wolters LA, Bottaro E, Nastruzzi C, Yang SC, Tsay SC, Hwu JR, Snijder EJ, van Hemert MJ. Antiviral Res. 2015 Sep;121:39-46.
- Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity. Peters HL, Jochmans D, de Wilde AH, Posthuma CC, Snijder EJ, Neyts J, Seley-Radtke KL. Bioorg Med Chem Lett. 2015 Aug 1;25(15):2923-6.
- Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, van den Hoogen BG, Neyts J, Snijder EJ. Antimicrob Agents Chemother. 2014 Aug;58(8):4875-84.
- Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. Delang L, Segura Guerrero N, Tas A, Quérat G, Pastorino B, Froeyen M, Dallmeier K, Jochmans D, Herdewijn P, Bello F, Snijder EJ, de Lamballerie X, Martina B, Neyts J, van Hemert MJ, Leyssen P. J Antimicrob Chemother. 2014 Oct;69(10):2770-84.
- Inhibition of dengue and chikungunya virus infection by RIG-I-mediated type I IFN-independent stimulation of the innate antiviral response. Olagnier D, Scholte FE, Chiang C, Albulescu IC, Nichols C, He Z, Lin R, Snijder EJ, van Hemert MJ, Hiscott J. J Virol. 2014; 88: 4180-94.
- MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW, Posthuma CC, van der Meer Y, Bárcena M, Haagmans BL, Snijder EJ, van den Hoogen BG. J Gen Virol. 2013; 94:1749-60.