A new journal publication provides a unifying hypothesis termed “Bradykinin Storm” based on the effects of coronavirus. We look into patent information for insights on the potential drug candidates and leading researchers.

Until recently, scientists and doctors have been baffled by the numerous ways that Covid-19 attacks the human body. The virus was initially classified as a respiratory disease that primarily infected a patient’s lungs. However, patients experienced a wide range of disparate symptoms from heart inflammation to the loss of the ability to smell and taste to “Covid toes”, skin lesions on the feet or hands of patients.

Fortunately, with the help of a supercomputer scientists may have found an explanation. A team of researchers led by Dan Jacobson, used the Summit supercomputer at the Oak Ridge National Laboratory in Tennessee to analyze genetic data from Covid-19 patients. This study helped the team devise a new theory about how Covid-19 attacks patients, which they have called the bradykinin hypothesis. The hypothesis explains many of the unusual symptoms of Covid-19 patents and even suggested potential treatments that already have FDA approval.

According to the study, Covid-19 first enters the body through ACE2 receptors in the nose. It then infects cells in other places where ACE2 is also present, such as the heart. This could explain the disease’s cardiac symptoms. Even more insidiously, Covid-19 then tricks the body into upregulating ACE2 receptors in places where they are not significantly expressed. This takeover of ACE2 receptors is where bradykinin fits into the puzzle. Bradykinin is a 9-amino acid peptide that helps to regulate blood pressure amongst its other functions. According to the study, ACE normally breaks down bradykinin, but the virus causes the body’s tools for regulating bradykinin to go wild and the body stops essentially breaking down bradykinin. Researchers have called this a bradykinin storm. According to the bradykinin hypothesis, it is this storm that is responsible for many of Covid-19’s varying symptoms.

As bradykinin builds up in the body, it makes the body’s blood vessels more prone to leaking. This obviously has a bad effect on a person’s lungs. As blood vessels start to leak, the lungs can fill with fluid. The team’s study also found that a bradykinin storm increases the production of hyaluronic acid (HLA) in the lungs. HLA absorbs fluids, which in turn forms a gel-like substance, that can greatly affect the intake of oxygen by the lungs. According to Jacobson, “it’s like trying to breathe through Jell-O”.

The bradykinin hypothesis is such a novel theory, one would not expect there to be many patents or journal publications related to targeting the bradykinin pathway for coronavirus treatment. A quick search revealed 887 patent families and 32,371 journal publications worldwide, where bradykinin and coronavirus was mentioned in the full text. The top 20 patent assignees are listed below.

Patents or journal publications related to targeting the bradykinin pathway for coronavirus treatment

One of the most alarming realizations of our study is the flat line in patent application filings related to bradykinin broadly in the last 20 years, as depicted below. This may be due to a lack of interest from the big players in investing into this well known pathway.

Patents related to targeting the bradykinin pathway

We can expect that there will be a significant increase in patent filings in this space now that the Bradykinin Hypothesis is now being linked to Covid-19 symptoms. Unfortunately, that does not help us today.

With that in mind we dug into the body of earlier patents and patent applications to see if there are any that might be relevant to the treatment of Covid-19. One interesting prior art reference is US20080159962A1 entitled, “Use of Inhibitors of the Renin-Angiotensin System for the Treatment of Lung Injuries” and assigned to IMBA-Institute Fur Molekulare Biotechnologie GMBH, of Vienna, Austria. The application was abandoned in 2010 and none of its family members were ever granted. What makes it particularly interesting is that it claimed the use of bradykinin receptor inhibitors for the treatment of severe acute lung injury or failure connected to infection with severe acute respiratory syndrome (SARS) coronavirus.

The medications described in the publication includes a list of potent bradykinin B1/B2 receptor antagonists:

B9958 Lys-Lys[Hyp3,Cpg5,dTic7,Cpg8]des-Arg9]-bradykinin
R914 and R715 AcLys-Lys([αMe]Phe5,D-βNal7,Ile8]des-Arg9-bradykinin and AcLys[D NaI7,Ile8][des-Arg9]-bradykinin
Icatibant; HOE140 DArg[Hyp3,Thi5,DTic7,Oic8]-bradykinin
Anatibant; LF160687 1-([2,4-dichloro-3-{([2,4-dimethylquinolin-8-yl]oxy)methyl}phenyl]sulphonyl)-N-(3-[{4-(aminomethyl)phenyl}carbonylamino)propyl)-2(S)-pyrrolidinecarboxamide
FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-(N-[2,4-dichloro-3 {(2-methyl-8-quinolinyl)oxymethyl}phenyl]-N-methylaminocarbonyl-methyl)acrylamide
WIN 64338 [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2-naphthyl)-1-oxopropyl]amino]phenyl]methyl]tributylphosphonium chloride monohydrochloride
Bradyzide (S)-1-[4-(4-benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl]pyrrolidine-2-carboxylic acid [2-[(2-dimethylaminoethyl)methylamino]ethyl]amide

Icatibant (sold under the brand name Firazyr) is an antagonist of bradykinin B2 receptors.

Another interesting publication is the expired U.S. patent US5240694 entitled, “Combined Antiviral and Antimediator Treatment of Common Colds” and listing the University of Virginia as the original assignee. This patent discusses the use of kinin (bradykinin and lysylbradykinin) pathway antagonists in a combination for the treatment of influenza virus and other cold viruses including coronavirus, parainfluenza virus, rhinovirus, adenovirus, and respiratory syncytial virus.

Hypotheses, particularly those that fit very well, rarely work out in medicine. However, with a bit of luck, we may find ourselves with another advanced treatment candidate.

Researchers may find that prior art patents will provide some guidance to their current work in developing better treatment options for Covid-19. With that in mind, we are making available the patent search results available for free. Contact us to receive your copy. Subscribe to our blog to receive our exclusive updates through email.

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