We have access to a diverse library of more than 4000 synthesized heterocyclic compounds and building blocks. Among them there are number of biologically active molecules that Vironova Medical have found and studied as perspective antiviral, anticancer or antiinflammation agents. Indolo[2,3-b]quinoxalines are the most investigated class of compounds that gave us several leads, such as B-220 or JBA-185 (antiviral and anticancer activity) and T-Rabeximod (antiinflamatory activity).
We are also using our thionation technology in our drug discovery process. We have found that in some cases thionated analogues of biologically active molecules possess very interesting properties including improved efficacy and ADME properties. VNFC045 and T-Rabeximod – the lead compounds in our Influenza and Rheumatoid Arthritis projects, are good examples of this approach.
Broad-spectrum antiviral activity of indolo[2,3-b]quinoxalines was first discovered about several decades ago against herpes family viruses: HSV-1, HSV-2, Cytomegalovirus (CMV) and Varicella zoster (VZV). Vironova Medical was working on lead optimization of indolo[2,3-b]quinoxaline derivatives for the treatment of Herpes labialis and Herpes genitalis, which are infections caused by herpes simplex virus-1 (HSV-1) and herpes simplex-2 (HSV-2) and developed B-220 as a candidate drug.
B-220 has a different mechanism of action compared to Acyclovir, inhibiting viral replication at different stages of the virus cycle (Harmenberg J et al. Antimicrob Agents Chemother. 1988 Nov; 32(11):1720-4). Selective intercalation with viral DNA was shown as major mechanism of drug action that allows to inhibit viral multiplication at an early point in the virus cycle.
Influenza is a highly contagious acute viral infection, which causes annual epidemics as well as recurring devastating pandemics of respiratory disease in both humans and animals. Typically, influenza spreads worldwide in seasonal epidemics resulting in an estimated 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths annually. The flu is caused by a family of enveloped viruses termed A, B and C, which possess a segmented, single-stranded negative RNA genome.
Vironova Medical´s project targeting influenza is based on novel derivatives of Nucleozin discovered by Kao et al. in 2010. Researchers have identified a compound which can aggregate the viral nucleoprotein and prevent its transport into the nucleus. The nucleoprotein plays critical roles in viral RNA replication and genome assembly. Nucleozin was shown to block replication of H1N1, H3N2, and H5N1 viruses in cell culture experiments and also to protect mice from lethal challenge with highly pathogenic avian influenza virus A H5N1. Nuclezin derivatives demonstrated good anti-Influenza effects, however very reduced efficacy against more recent swine flu H1N1-variant (Gerritz et al. 2011). The study shows that the nucleoprotein is a viable drug target and could lead to the development of new treatments to control the impact of future influenza outbreaks.
A library of Nucleozin derivatives containing a novel heterocyclic core and substituents, resulting in improved ADME properties, were prepared by Vironova Medical together their thionated analouges. The project was initiated as part of an EU founded program.
When the Covid-19 pandemic emerged in early 2020, biomedical researchers scrambled to find treatments and drugs that could save the lives of people infected with the coronavirus. A serious complication of COVID-19 infection is the massive synthesis and release of cytokines and chemokines in some patients. This excessive synthesis of pro-inflammatory cytokines results in a state of hyper cytokinemia (also known as a cytokine storm) and can lead to severe outcomes such as multiple organ failure. From previous studies on influenza, we have observed that our compounds help to suppress the proinflammatory response in vivo. This dual antiviral and reduced cytokine production effect may indicate a possible role in preventing serious or fatal distress associated with hyper cytokinemia as well. Having this knowledge we decided to join the race and test some of our active influenza compounds against SARS-CoV-2. Preliminary observations indicate that they indeed have an antiviral effect in cell-based assays. The project is in early drug discovery phase in collaboration with The University of Tennessee, USA.
Inflammation (Reumatoid Arthritis)
Application of Vironova Medical´s thionation technology to a series of indoloquinoxalines produced a series of thionated analogues of Rabeximod that shows substantial ability to significantly reduce arthritis incidence in animal models.
Rabeximod is an indolo[2,3-b]quinoxaline derivative discovered by Prof. Jan Bergman and patented by OxyPharma AB as anti-inflammatory agent useful (WO2005123741) for the treatment of autoimmune disease. In 2018 the Rabeximod patent was acquired by Cyxone AB, and Phase IIb trials were recently initiated. Rabeximod impaired monocyte differentiation into monocyte-derived dendritic cells and pro-inflammatory allostimulated macrophages. Rabeximod reduces the severity of arthritis and can efficiently prevent arthritis during the time window when TLR2 or TLR4 ligands activate inflammatory macrophages in mice.
Vironova Medical have filed a patent in 2020 for the use of thionated Rabeximod against autoimmun disorders such as Reumatiod Arthritis.
Vironova Medical collaborates with National Institute of Health (NIH) and their NCI-60 human cancer cell line screening program. To date more than 250 compounds of different structural classes from our library have been screened against a panel of cancer cell lines. About 30 compounds have been selected for further investigation by NIH. Most compounds originate from the indolo[2,3-b]quinoxaline structural family (B-220 and its analogues).
The project has now entered the hit-to-lead phase of drug discovery process.
Intellectual property (IP)
Vironova Medical strives to protect all technology and products developed. Patent applications are submitted in all relevant markets for both our chemical process technology and our drug candidates. Currently Vironova Medical have five different patent families including both active patents and patent applications.