NOVIRUSES2BRAIN Overview

Summary

Viruses that infect the brain and other parts of the central nervous system are a worldwide threat of terrible dimensions. Viruses such as Zika, Dengue, Chikungunya, HIV or measles, for instance, are responsible for thousands of victims severely impaired at neurological level each year in the world. The most recent large scale threat in this domain was a Zika virus outbreak in

South America. Zika virus, like Dengue virus or Chikungunya virus, is spread mainly by mosquitos of the genus Aedes. While Dengue and Chikungunya viruses, as many others, might causes diseases with severe neurological disorders, Zika virus is much more dreadful in this regard. When a pregnant woman is infected, the virus is able to translocate the blood-placental barrier and then the developing blood-brain barrier of the foetus, causing microcephaly and serious neurological disorders to newly born babies. Although co-infections with Aedes-borne viruses, such as the above mentioned Zika, Dengue and Chikungunya viruses, are likely because several viral species coexist in the same vector, the classical drug development strategies completely overlook this striking reality. Moreover, additional co-infections with HIV and measles virus, using other routes of infection, are also possible. A drug able to target a very large spectrum of viral species is urgently needed. Importantly, this drug must be able to traverse the blood-brain barrier and reach the viruses accumulated in the brain. NOVIRUSES2BRAIN is a project that aims at finding and selecting drug leads that are both efficacious and able to translocate the blood- placental and blood-brain barriers so that Zika, Dengue, Chikungunya and other viruses can be targeted across barriers, including during pregnancy. The project gathers the expertise of medicinal chemists, biochemists, drug development specialists and virologists to create drug leads able to clear all viral species from brain simultaneously.

Beneficiaries and partners

Participant Name Short name Country PI
Beneficiaries
Instituto de Medicina Molecular
João Lobo Antunes
iMM Portugal Miguel Castanho
Universidad Pompeu Fabra UPF Spain David Andreu
Synovo Gmbh Synovo Germany Michael Burnet
Partners
Universidade Federal do Rio de Janeiro UFRJ Brazil Andrea Da Poian

Details

Title ''One size fits all'' unique drug to eradicate multiple viral species simultaneously from the central nervous system of co-infected individuals
Acronym NOVIRUSES2BRAIN
Funding Agency European Commission
Funding Programme H2020-EU.1.2.1. - FET Open
Call / Topic FETOPEN-01-2018-2019-2020 - FET-Open Challenging Current Thinking
Grant agreement ID 828774
Start date 2019.09.01
Duration 48 months
Total investment EU contribution: 3 933 965,63€
Project Coordinator Miguel Castanho (Instituto de Medicina Molecular João Lobo Antunes (iMM), Portugal)
Project Beneficiaries - Instituto de Medicina Molecular João Lobo Antunes (iMM), Portugal
- Universidad Pompeu Fabra (UPF), Spain
- Synovo Gmbh (Synovo), Germany
Project Partners - Universidade Federal do Rio de Janeiro (UFRJ), Brazil
CORDIS https://cordis.europa.eu/project/rcn/220067/factsheet/en

Scientific Background

  • Dengue and Chikungunya viruses might cause neurological disorders, but Zika virus is even more dreadful. When a pregnant woman is infected, Zika virus is able to translocate the blood-placental barrier and the developing blood-brain barrier of the fetus, causing microcephaly and serious neurological disorders to newly born babies, in addition to being potentially harmful to the mother (Yuan et al., 2017).

 

  • Zika, Dengue and Chikungunya viruses are spread by mosquitos of the genus Aedes. Many of the world tropical regions provide high suitability to Aedes Over the last 30 years, due to climate changes, the distribution and public health impact of these viruses have increased dramatically, causing a global threat (Leta et al., 2018).

 

  • Although COVID-19 is considered to be a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system. Although recently discovered, it was already showed that SARS-CoV-2 virus is present in human and mouse brain neurons (Song et al., 2020).

 

  • Co-infections with Aedes viruses, such as Zika, Dengue and Chikungunya viruses, are likely because several viral species can co-exist in the same vector. Still, the classical drug development strategies overlook this striking reality. Moreover, co-infections with HIV, SARS-CoV-2 and measles viruses are also possible, all of them able to accumulate in the brain (Salvo et al., 2020).

 

  • Recently Miguel Castanho’s lab described cell-penetrating peptides (CPP) with the ability to translocate the blood-brain barrier. The peptides obtained from the dengue virus capsid protein show robust brain uptake and appear as ideal shuttles across this physiological barrier (Neves et al., 2017) (Figure 1).

 

Figure 1 – Dengue virus capsid protein (DEN2C) sequence. DEN2C is a 12 kDa protein, with 100 amino acid residues. The protein is formed by four helical domains, α1, α2, α3, and α4, designated PepH1, PepH2, PepH3, and PepH4, respectively, which were studied as translocators of blood-brain barrier. (Neves et al., 2017)

 

  • In vitro models will be used to investigate the ability of molecules to cross the blood brain barrier (Neves-Coelho et al., 2017) (Figure 2).

 

Figure 2 – In vitro blood brain barrier model consists of a transwell system with an insert in which cells are grown in two separate chambers. The insert, or apical side, corresponds to the blood side, while the basolateral side (bottom chamber) corresponds to the brain side (Neves-Coelho et al., 2017)

 

References:

Leta S, Beyene TJ, De Clercq EM, et al. (2018) Int J Infect Dis., 67:25-35.

Neves-Coelho S, Eleutério RP, Enguita FJ, et al., (2017), Molecules, 22(10):1753.

Neves V, Aires-da-Silva F, Morais M, et al. (2017) ACS Chem. Biol., 12(5):1257–1268.

Salvo CP, Lella ND, López FS, et al. (2020) Medicina, 80(Supl. VI):94-96.

Song E, Zhang C, Israelow B, et al. (2020) J Exp Med., 218(3):e20202135.

Yuan L, Huang X-Y, Liu, Z-Y et al. (2017) Science, 358(6365):933-936.