COVID-19 Intranasal Drugs: Australian And British Researchers Exploring TLR2/6 Agonist INNA-051 As An Intranasal Prophylaxis Against COVID-19
COVID-19 Intranasal Drugs
: Researchers from the National Infection Service-UK, Ena Respiratory, Melbourne-Australia, The University of Melbourne-Australia, University of Newcastle-Australia and Oxford University-UK are exploring the usage of TLR2/6 Agonist INNA-051 as an intranasal prophylaxis against COVID-19.
To date their vivo studies involving animal models showed that the TLR2 agonist reduces SARS-CoV-2 in upper respiratory tract of ferret model.
The research findings are published on a preprint server and have yet to be peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.09.25.309914v1
To date it has been found necessary to boost the human respiratory system's antiviral immune defenses to reduce SARS-CoV-2 viral shedding in the upper respiratory tract (URT) and control the viral transmission.
It has been proposed by the study team that a prophylactic intranasal administration of the TLR2/6 agonist INNA-051 exhibits viral reduction and this offers a promising approach for possible prevention and management of SARS-CoV-2 infection, particularly useful to individuals at elevated risk of community transmission.
The deadly respiratory virus, SARS-CoV-2, causing the current COVID-19 disease pandemic, initially infects the upper respiratory tract (URT).
Infected individuals may be symptomatic, pre- or asymptomatic, spreading the virus nonetheless.
It was found that asymptomatic individuals shed the virus and transmit the disease longer than those with symptoms. It is essential to restrict the initial replication of the virus in URT to prevent the progression of the disease.
The study team demonstrated that prophylactic intra-nasal administration of TLR2/6 (toll-like receptor) agonist, INNA-051, reduces viral RNA in the nose and throat, in a ferret model.
The study findings supports developing a therapy based on prophylactic TLR2/6 innate immune response in the URT against the SARS-CoV-2 virus.
The researchers identified a series of novel synthetic molecules named the INNA compounds that have been developed with TLR2/6 agonist properties.
These INNA compounds are safe, antiviral drug candidates specifically designed to exert TLR2-mediated pharmacological activity on the mucosal epithelium.
INNA-051 belongs to a series of closely-related, pegylated synthetic analogues of the diacylated lipopeptide, S-[2,3-bis(palmitoyl oxy)propyl] cysteine (Pam2Cys) ( compound series), with selective TLR2/TLR6 agonist activity.
Various human coronavirus have emerged over the past two decades through transmission via an intermediate animal host. Outbreaks across the world have caused significant respiratory morbidity and mortality.
Both the the SARS (in Asia between 2002 to 2004) or MERS CoVs (in Saudi Arabia in 2012) are highly pathogenic.
However since emerging in Wuhan, China, in December 2019, SARS-CoV-2 infections have proven to be more infectious and complicated and have caused mild to severe broad spectrum respiratory symptoms, and life-threatening mostly in the hig
h-risk population such as the elderly.
It is well known that all these respiratory coronaviruses primarily spread through airborne routes ie respiratory droplets from infected individuals.
Also it is known that the initial site of infection is the epithelium of the upper respiratory tract or URT.
The upper respiratory tract expresses abundant nasal epithelial cell receptors of the SARS-CoV-2 virus ie the angiotensin-converting enzyme 2 (ACE2). To find a topical treatment of the URT, which will boost antiviral immunity and restrict viral replication, the authors identified a synthetic agonist of TLR molecules.
The TLR 2 receptors dimerize with TLR1 or TLR6 to recognize a range of commensal and pathogenic microbial molecules; its activation is tightly regulated to maintain immune homeostasis. It is noted that unlike other TLR molecules used for possible innate immunity boost, TLR2/6 agonists of the INNA compound series do not directly activate Type-1 interferons.
Studies have already reported that the INNA compounds protect from lethal influenza virus infection, prevent viral transmission and secondary bacterial super-infections in mouse disease models.
In the research, the study team determined the TLR2/6 agonists' activity against the SAR-CoV-2 virus in vivo
. They used prophylactic intra-nasal administration of the novel compound INNA-051, in a SARS-CoV-2 challenge ferret model.
Typically, Ferrets are commonly used as models for human respiratory virus-induced diseases to evaluate the efficacy of related vaccines and drugs. Ferrets are good models for this kind of study because they express the virus entry receptor - ACE2, in their airways. Upon infection with the SAR-CoV-2 virus, the virus replication occurs in their URT, and the ferret exhibit dose-dependent viral shedding.
The administration of INNA-051 in the absence of infection did not induce any observable inflammation in the animal; change in body temperature revealed some variation between treatment groups. There was no change in the bodyweight of the animal. Obvious clinical signs of the COVID-19 disease were also not found in ferrets, except the robust respiratory replication of viral in URT. Nasal wash and throat swabs were collected from the ferrets for viral RNA tests.
Importantly, the observed RNA viral reduction was significant: 10 fold and >10 fold for nasal and throat samples, respectively, in the group with high dose 0f INNA-051. The reduction of virus observed in the group of animals (with a low dose of INNA-051) in throat swabs is 24 fold (96% reduction) and in the nasal wash is 15 fold (93% reduction) compared to untreated animals.
Lung tissue samples were analyzed to detect the SARS-CoV-2 virus beyond the upper respiratory tract (URT). Viral RNA was not detectable. The significant reduction of URT viral RNA levels are observed, this implies airway immunity and enhanced antiviral host defense.
It should be noted that many drugs may exhibit a reduction in clinical disease, but do not reduce the virus load and help halt the viral transmission.
Thus, it is crucial to develop a drug that rapidly boosts innate immunity at the primary site of respiratory infection.
The study team acknowledges that the ferret SARS-CoV-2 model has its limitations, not representing the severe spectrum of COVID-19 disease. They are, however, positive of the encouraging prophylactic results observed in this study. They report a predictive value of antiviral effectiveness and its translation into human infectious disease.
Interestingly the antiviral respiratory prophylactic drug, INNA-051, has many advantages: fast-acting to protect, little or no antiviral resistance, option to self-administer, and non-prohibitive cost for large-scale manufacturing. This TLR2/6 agonist INNA-051 can also be used as complementary to potential vaccination programs.
The research findings provides evidence for the first time to support a novel approach of arresting SARS-CoV-2 virus transmission by prophylactic intra-nasal administration of INNA-051; this is based on viral shedding analysis in an in vivo
SARS-CoV-2 infection model.
In conclusion, the study findings provides evidence that prophylactic intranasal administration of the TLR2/6 agonist INNA-051 offers a promising approach for prevention and management of SARS-CoV-2 infection that can be used as a stand-alone method of antiviral prophylaxis and is complimentary to potential vaccination programs.
This approach is particularly appealing to individuals at elevated risk of community transmission such as healthcare professionals ie doctors and nurses or those at risk of development of severe disease, including vulnerable communities, the elderly, the immunocompromised and those with existing comorbidities
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