(The regular readers of these threads will not find much different in this post compared to my other notes on BIT036, apart from a brief mention regarding the recent MontPellier paper. I am still working on that paper and will add to the threads in due course).
Many researchers around the world are dedicating themselves to finding a cure for COVID-19, the acute respiratory disease caused by the virus, SARS-CoV-2. Many of these researchers post their results on the BioRxiv and MedRxiv preprint servers for biology and medicine, operated by the Cold Spring Harbour Laboratory, New York. By early April, there were more than 1100 papers published on the servers dedicated to finding cures for COVID-19. This publishing system provides an ‘internet speed’ ability for new research to be made available for peer review.
Some of this research has suggested that small molecule drugs inhibiting functions in the essential E Protein of the virus, which is part of the viral replication process, is a possible solution for a cure. The small E Protein is one of the four essential proteins that make up the core of all RNA coronaviruses, and is the specialized field of Biotron, who made a unique discovery about E when it first commenced work on the first SARS outbreak in 2002. This discovery demonstrated for the first time that the E Protein is a viroporin, that is, a cell that enables electrical ion activity to pass through cell membranes and is part of the viral replication process. Since then, much research has continued worldwide using the ion channelling technology within RNA viruses.
Once SARS was contained, Biotron focused on HIV, and in late 2018, reached a significant milestone in ‘eradicating’ HIV with a ‘vaccine-like’ effect. However, phase 3 trials are yet to begin, but should do so in 2020 in partnership with a major pharmaceutical company.
The mention of this successful, yet incomplete HIV research, is potentially notable for finding a cure for COVID-19, as it uses this same ion channelling technology and compounds that have been suggested by other researchers.
One such research paper coming from the King Abdul University of Science and Technology in Saudi Arabia,published on the 17th February,[ii]identified several compounds as potential drug candidates, some of which belong to Biotron. They are Amantadineand Hexamethylene amiloride, which have been used in conjunction with Biotron’s BIT225, their main drug candidate for treating HIV.[iii]
The Saudi researchers performed a comparative pangenomic analysis of all the sequences of human coronaviruses to reveal that, among the core essential gene clusters, there are certain identical sequences in the E Proteins of both SARS-Cov-1 and SARS-CoV-2. They write:
‘The envelope protein E shows a variant shared by SARSand SARS-Cov2 with two completely-conserved key functional features, anion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine stormthat activates the inflammasome, leading to increased edema in lungs causingthe acute respiratory distress syndrome (ARDS), the leading cause of death inSARS-CoV-1 and SARS-CoV-2 infection.’ [iv]
When Biotron made their unique discovery on the viroporin E Protein when working with SARS, they also achieved to inhibit the ion channelling activity, and this work was co-incidently patented at the same time that the new strain of SARS was forming in December 2019. To appreciate the potential importance of Biotron’s E Protein inhibitors, it is worth considering that the same technology is what they have utilized in their successful HIV program thus far. The inference that follows is, if the ion channelling inhibiting compounds that have recently patented showed efficacy in all the human coronaviruses, including SARS1, then it is possible that they will work in SARS-CoV-2, including possibly BIT225, which has been beneficial in treating HIV patients.
How could such an outcome be achieved? The Saudi Paper goers on to state how Biotron’s compounds could be a solution to the pandemic:
“Studies on SARS-CoV-1 demonstrated that the E proteinuses the IC (ion channelling) and PBM (PDZ-binding motif) to trigger a cytokine storm thatactivates the inflammasome, leading to increased edema in lungs. Ultimatelythese events result in ARDS , a leading cause of death in SARS-CoV-1 andSARSCoV-2 infection. However, the drugs Amantadine, Hexamethylene amiloride andalso BIT225 (BIT225 is in clinical trials) completely block the IC activity ofSARS-CoV-19, and restrict its reproduction, leading to better survival of theanimal host.” [v]
Interestingly though for what the Saudi Paper does not reveal, is that Biotron has other compounds that have shown efficacy in inhibiting ion channel activity, notably BIT036 – cinnamoylguanidine - which was revealed in Biotron’s US Patent, and that the Saudi’s were not aware of. This compound and its derivatives were used against all other human coronavirus strains, including SARS-CoV-1, and demonstrated effective ion channel blocking as can be seen in the below diagrams. [vi]
The diagram shows the difference in ion channelling in a normal E Protein (top line) and one treated with BIT036 (bottom line). The first line consists of squiggly lines showing the electrical activity of the wild SARS1 E protein, whereas the second shows it after being treated with BIT036. Notice the absence of electrical activity.
Whether or not this activity will be useful in developing a cure for COVID-19 is yet to be revealed, but if the success that Biotron has had using the technology to treat HIV is anything to go by, then the forthcoming COVID results may have more chance than not in being successful.
But it is not only the Saudi’s who have realized that E protein inhibitors may be a treatment for COVID-19. On April 9th, 2020, another research paper was released on the BioRxiv server from MontPellier University in France, and this also showed important similarities within the E protein of SARS1 and SARS2, and suggested that small molecule compounds able to inhibit E Protein activity require “urgent assessment.”[vii]
‘The identification of smallmolecules (or the repurposing of existing drugs) able to disrupt SARS-CoV-2 EBH3-mediated interactions might provide a targeted therapeutic approach forCOVID-19 treatment. Recombinant SARS-CoV-2 expressing an E protein with adeleted or mutated BH3-like motif might also be of interest for the design of alive, attenuated vaccine.’[viii]
What is significant about the Montpellier paper within the presentdiscussion is that their identification of using small molecule drugs thatdisrupt the E Protein is exactly what Biotron’s compounds do, not only by theirmain HIV drug candidate, BIT225, but also more than thirty other compounds thatthey have in their small molecule library.Significantly, Biotron’s US patent was published on December 26th 2019, for compounds and methods for treating Coronaviruses.
The precise compound used in many of their tests against many ofthe human strains of coronaviruses, including SARS-Cov-1, as mentioned above, wascinnamoylguanidine,[ix]identified as BIT036.
Presently then,we can only wait to see what Biotron’s latest results for testing theircompounds against SARS-CoV-2 will reveal, which will hopefully arrive by the end ofApril, 2020.
[vi]http://www.freepatentsonline.com/20190389816.pdf
