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''One size fits all'' unique drug to eradicate multiple viral species simultaneously from the central nervous system of co-infected individuals

Periodic Reporting for period 1 - NOVIRUSES2BRAIN (''One size fits all'' unique drug to eradicate multiple viral species simultaneously from the central nervous system of co-infected individuals)

Reporting period: 2019-09-01 to 2020-11-30

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, and more recently the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are responsible for thousands of victims severely impaired at neurological level each year in the world. Besides the pandemic caused by SARS-CoV-2, one of the most recent large scale threats in this domain was a Zika virus outbreak in South America. Zika, Dengue and Chikungunya viruses are spread mainly by mosquitoes of the Aedes genus. 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 (frontier between blood and placenta) and then the developing blood-brain barrier (frontier between blood and brain cells) 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 may coexist in the same mosquito, the classical drug development strategies completely overlook the reality of co-infection for these viruses. Moreover, additional co-infections with HIV, SARS-CoV-2 and measles virus, using other routes of infection, are also possible. A drug able to target a very large spectrum of viral species, simultaneously, is urgently needed. Importantly, this drug must be able to traverse the blood-brain barrier and reach the viruses accumulated in the brain.
NOVIRUSES2BRAIN aims to develop drug leads that are both efficacious and able to cross the blood-placental and blood-brain barriers so that Zika, Dengue, Chikungunya and other viruses, such as the recently discovered SARS-CoV-2, can be targeted across barriers, including during pregnancy.
NOVIRUSES2BRAIN aims to develop conjugated molecules capable of cross the blood-placental and blood-brain barriers, and be active against Zika, Dengue, HIV and SARS-CoV-2 viruses in brain.
We have been designing and synthetizing an initial pool of molecules able to translocate the blood-placental and blood-brain barriers and to have antiviral activity.
To evaluate the ability of the conjugates to cross the blood-brain barrier as well as their impact in the integrity of the blood-brain barrier (blood-brain barrier’s quality of maintaining its perfect condition), the conjugates were tested in in vitro blood-brain barrier models using mouse and human brain cell lines. Some of the molecules have traversed efficiently the blood-brain barrier models without affecting their integrity. In addition, the antiviral efficacy of the conjugates was evaluated against Dengue virus (DENV), Zika virus (ZIKV), HIV and SARS-CoV-2 viruses. The activity of the conjugates was evaluated by determining their half maximal inhibitory concentration (IC50) or the 90% of the maximum inhibitory concentration (IC90) of DENV, ZIKV, HIV and SARS-CoV-2 viruses infection using cell lines.
Finally, the toxicity of the conjugates was studied in different cell lines in order to estimate the appropriate dose ranges to be used in the tests of antiviral efficiency in vivo. The cytotoxicity of the conjugates in brain, neuronal, lung, kidney and liver cells lines was evaluated using viability assays. The concentration of the conjugates required to reduce cell viability by 50% (CC50) was calculated and taken into consideration to select the conjugates to be used in the following tasks.
To evaluate the penetration of the conjugates in brain, in vivo preliminary pharmacokinetic studies in mouse models were implemented. The analysis of their toxicity and biodistribution (blood, heart, cerebrospinal fluid, liver, kidney, and brain) over time was carried out.
NOVIRUSES2BRAIN uses a robust approach based on a unique synergy of medicinal chemistry, biochemistry/biophysics and in vivo virology studies. Chemotherapy against Zika virus and other viruses that reach the brain will definitely be a major achievement in medicinal chemistry worldwide. There are no drugs available against Zika and many other Aedes-borne viruses thus; there is an urgent need for novel antiviral drugs with extremely broad spectrum of action. We strongly believe that the project will translate into effective drug leads feeding into the rather meager pipeline currently available for fighting Zika and related viruses infection.
In the past, we identified molecules with antiviral activity and others molecules with proven capability of crossing biological barriers such as the blood-brain barrier. In tune with this, NOVIRUSES2BRAIN aims to develop a totally innovative chemotherapeutic strategy combining these two types of molecules.
Until now, we were able to develop an initial pool of conjugated molecules, some of which are able to cross biological barriers and maintain antiviral activity while having low cytotoxicity in brain, lung, kidney and liver cells lines. Moreover, we implemented in vivo assays to investigate conjugates’ brain uptake, organ distribution and toxicity.
The next steps will be to select the best performing conjugates, which will be used in the tasks involving in vivo work and animal models. In the end of the project, we expect to have identified conjugates with therapeutic potential that can be translated to industry.
This project will have a huge impact because: (i) New drug leads against viruses that reach the brain will be generated and no alternatives exist for chemotherapy, which will create the benefit of patients and economy; (ii) The drug leads to be generated will be used in cases of co-infection with different mosquito-borne diseases, which is deemed important due to the expansion of Aedes mosquito populations in several continents, including Europe and North America; (iii) Europe will reinforce its capacity to generate, screen, and develop antiviral drugs. Given the structural similarity between these viruses and SARS-CoV-2, this virus is also being addressed, constituting in itself a fourth high gain goal of the project.
These drug leads might awaken the interest of the pharma industry and be translated into effective broad-spectrum antivirals. The impact of such results on improved health and social well-being will be remarkable. The risk/gain balance is highly positive as the gain for science, society, and economy is immense.
The NOVIRUSES2BRAIN logo includes the project acronym and two graphic elements: a schematic represen