Therapeutic use of gold containing compounds
Prior to 1990, parenteral gold was the “gold” standard for the therapy of Rheumatoid Arthritis (RA). The main effector of pharmacological activity of all gold containing drugs is the gold-1+-ion, while the organic counterion determines the bioavailability. On the molecular level, the reactivity of gold compounds with thiol groups appears to be the predominant factor. In addition, there is the potential for interaction with proton binding sites of proteins. A pivotal function of cysteine is the conformational stabilization of the tertiary and quaternary structure of proteins by the formation of disulfide-bridges. Functional important domains of proteins very often contain cysteine, which makes this amino acid crucially important for the function of the respective receptors and enzymes. The gold-1- ion prevents this functional role of cysteine.
Aurothioglucose has been a widely used gold-compound. Despite its high efficacy, the use of gold drugs has steadily decreased during the last decades because of the successful introduction of biologicals for the treatment of rheumatic diseases.
Aurothioglucose (ATG) was used as intramuscular injections of an emulsion in oil, as a systemically administered drug.
Despite their replacement in the therapy of rheumatic diseases, gold compounds have been investigated in different indications in recent years. A high potential for new applications in the treatment of some forms of cancer, parasitic infections, bacterial infections, viral infections and even neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s are in discussion and clinical trials are ongoing (Roder 2015).
The anti-viral activity of gold 1+
The anti-inflammatory and immune modulatory effects of gold1+
Many indications of current interest are linked to the high anti-inflammatory efficacy of gold containing compounds, which is related both to inhibition of COX-2 and the nuclear factor NFƙ-B, which serves as a pivotal mediator of inflammatory responses (Liu et al., 2017). It could be shown that gold suppresses NF-ƙB binding activity. This mechanism results in a subsequently reduced production of pro-inflammatory cytokines, most notably TNF-α, interleukin-1 and interleukin-6.
In vitro application of aurothioglucose led to the inhibition of IL-6 and IL-8 via inhibition of NfkB. (Yoshida et al., 1999). Topical cutaneous application of auranofin significantly reduced levels of proinflammatory cytokines TNFα, IL-6, IL-1β and MCP-1 (Thangamani et al., 2016 b). A mouse model for ARDS showed that lung injury (edema, inflammation) following exposure to LPS/hyperoxia can be significantly attenuated by aurothioglucose and survival rate improved (Britt et al, 2014).
Immune modulatory effects
On the subsequent T-cell level, gold has been shown to induce an upregulation of IL-4 mRNA, resulting in a shift of the T-cell population to the Th2 phenotype. Th1 cells activate macrophages and produce INF-y, while Th2 cells suppress the proinflammatory TH1 cells. Thus, the activation of pro-inflammatory T-cells is inhibited. (Burmester, 2001; Yoshida et al., 1999)
In nearly every area of immunology inhibiting actions of gold could be documented; however, it is still unclear if there is a common denominator or if there are parallel modes of actions which are independent of each other. Analyzing the actions of gold in the different phases of an immune reaction suggested that gold plays an important role already in the initiation, namely the uptake and presentation of foreign antigens. Thus, gold is taken up by the macrophages and stored in the lysosomes which are called aureosomes where gold inhibits antigen processing. In particular, peptide antigens, which contain sulfur such as cysteine and methionine, are important (Burmester, 2001).
The antimicrobial activity of gold1+
In search for therapies against multi-resistant bacteria gold compounds have also been shown to possess high anti-microbial and anti-biofilm activity (Miró-Canturri et al., 2019).
Auranofin has shown greater activity against a wide range of Gram-positive bacteria including S. pneumoniae, S. aureus, Enterococcus faecium, E. faecalis, and Streptococcus agalactiae in monotherapy when compared with vancomycin or linezolid (Aguinagalde et al., 2015; Thangamani et al., 2016a,b). In vivo, auranofin and its analogs have demonstrated therapeutic efficacy in different experimental models against multi-resistant Staphylococcus aureus such as MRSA septicemic infection, MRSA skin infection, MRSA implant infection model (a model involving mesh-associated biofilm), and MRSA intramuscular infection model (Aguinagalde et al., 2015; Thangamani et al., 2016 a,b). The mode of action of auranofin against S. aureus has been deciphered using the macromolecular biosynthesis assay which showed that auranofin acts on the inhibition of DNA replication and protein synthesis, downregulating the toxin production, and disrupts biofilms (Thangamani et al., 2016 a, b).
Aurodual®
Our own research could confirm many of the mentioned anti-viral, anti-inflammatory, immune modulatory and anti-bacterial effects for aurothioglucose alone and in combination with N-acetycystein. The dual combination drug of aurothioglucose and N-acetycystein will be called Aurodual®.
Aurodual® - a unique compound for the treatment of viral infections
By use of ATG a systems-pharmacological approach can be realized. In contrast to all other therapeutic concepts under investigation ATG is directed against several targets of different pathogenic origin and is effective in different phases of the disease. Each of the mechanisms presented below will contribute to the therapeutic success.
The efficacy of Aurodual® is based e. g. on
- The interaction of ATG with the Corona-virus S-protein, which is crucial for the fusion of virus and host cells
- The interaction of ATG with the viral envelope-protein, which is necessary for virus assembly and release
- Inhibition of COX induced inflammatory processes
- Inhibition of NFkB dependent immunological responses
- Prevention of bacterial superinfections
- Biofilm disruption
This multi-target action is related to the interaction of the gold1+ ion with specific sites at proteins, which are rich in cysteine. With corona viruses specifically the following target regions have been recognized up to now:
- A cysteine-rich C-terminal region of the Cov-2-spike protein (S) is essential for the fusion of
the virus with the host epithelial cell (Chang et al, 2000, Broer et al., 2006). - A cysteine-rich domain close to the transmembrane domain of the envelope protein (E) of
Corona viruses is essential for virus replication and assembly (Schoeman and Fielding, 2019).
Aurodual® has shown strong neutralization (killing) of RSV, Covid-19 and Influenza A/B virus in standard neutralization plaque assays over one hour.
Aurodual® – triple efficacy for the treatment of viral infection
In the clinical application, the comprehensive action based on anti-inflammatory, anti-viral, and anti-bacterial properties of this compound will be particularly beneficial in severe courses of the disease.
- The specific ATG antiviral activity during infection
- The combination of this activity with strong anti-inflammatory and immune modulatory properties based on the inhibition of the key driver NFkB targeting two pivotal pathogenetic factors.
- Down-regulation of the excessive reaction of the host´s immune system (e.g. IL-1b, IL-6)
- Concomitant attack on the virus on various levels and prevention of further replication
- An additional benefit via the antibacterial activity of ATG, which can also overcome biofilm formation and wide-spread resistance mechanisms
Inhalative therapy for optimum efficacy and minimization of side effects
In contrast to earlier applications of gold compounds (including recent and ongoing clinical trials) and the majority of all currently investigated drugs in the context of viral infections an additional specificity of the approach of Aurovir Pharma GmbH with Aurodual® is related to the fact, that the drug is delivered by inhalation of an aerosol directly into the lung, which is the most affected and critical organ system. Thereby, maximum activity can be achieved with very low quantities of ATG and a minimum of systemic burden. Drug-drug interactions and adverse side effects should be kept at a minimum. The overall duration of treatment compared to high-dose application in rheumatic disease will be very short with ca. 7-10 days. Therefore, we expect the drug to be well tolerated and without safety issues of the long-term systemic use.
In patients in intensive care, aqueous solutions of ATG can be simply added via spray nozzles to the respirator. For patients breathing on their own several types of inhaling systems are available (nebulizers, inhalers).
