Can Covid 19 And Human Ace2 Receptor Interaction Be Stopped By Lysine And Lysne Analouges

[SAFFRONKNIGHT]

CAN LYSINE AND LYSINE ANALOUGES HAVE POTENTIAL ROLE IN PREVENTING VIRAL SPIKE PROTEIN AND ANGIOTENSIN CONVERTING ENZYME 2 (ACE2) ECTODOMAIN INTERACTION

An OBSERVATION

 

 

 

INTRODUCTION:

 

COVID-19 or SARS COV 2, is a beta coronavirus, with a positive sense single stranded RNA, responsible for the current 2020 Coronavirus pandemic in about 180+ countries, leading to more than a million cases , 50,000+ deaths.

The world scientific community has been quick to respond with valuable research papers, candidate drug trials and vaccine development programmes.

Many of the drugs, currently approved by the world FDAs have been able to cure the patients, but with prolonged treatment time and comparatively non responsive to patients with co morbidities, or to the complications arising from the infection ( cytokine storm, septic shock, renal failure, ARDS).

Such scenario is very clear in countries like Italy, Spain, and recently The USA.

 

CONTENTS:

1. PATHOGENESIS OF RECEPTOR INTERACTION AND FUNCTION OF LYSINE
2. MECHANISM OF LYSINE ANALOUGES.
3. CONCLUSION

 

 

 

 

 

PATHOGENESIS OF RECEPTOR INTERACTON AND FUNCTION OF LYSINE

SARS COV 1 and SARS COV 2 have been found to target the same human ACE2 receptors as entry points to the cell. Human ACE2 is expressed  in Lungs , kidneys  and also in the CNS.

According to the studies published in (https://doi.org/10.1007/s00134-020-05985-9)

( Haibo Zhang1,3,6 , Josef M. Penninger4,5, Yimin Li3, Nanshan Zhong3 and Arthur S. Slutsky1,2,3*)

 

“There are many similarities of SARS-CoV-2 with the original SARS-CoV. Using computer modeling, Xu et al. [6] found that the spike proteins of SARS-CoV-2 and SARS-CoV have almost identical 3-D structures in the

receptor-binding domain that maintains van der Waals forces. SARS-CoV spike protein has a strong binding affinity to human ACE2, based on biochemical interaction studies and crystal structure analysis [7]. SARSCoV-2 and SARS-CoV spike proteins share 76.5% identity in amino acid sequences [6] and, importantly, the SARSCoV-2 and SARS-CoV spike proteins have a high degree of homology [6, 7]. Wan et al. [4] reported that residue 394 (glutamine) in the SARS-CoV-2 receptor-binding domain (RBD), corresponding to residue 479 in SARS-CoV, can be recognized by the critical lysine 31 on the human ACE2 receptor [8]. Further analysis even suggested that SARS-CoV-2 recognizes human ACE2 more efficiently than SARS-CoV increasing the ability of SARS-CoV-2 to transmit from person to person [4]. Thus, the SARS-CoV-2 spike protein was predicted to also have a strong binding affinity to human ACE2. This similarity with SARS-CoV is critical because ACE2 is a functional SARS-CoV receptor in vitro [9] and in vivo [10]. It is required for host cell entry and subsequent viral replication. Overexpression of human ACE2 enhanced disease severity in a mouse model of SARS-CoV infection, demonstrating that viral entry into cells is a critical step [11]; injecting SARS-CoV spike into mice worsened lung injury. Critically, this injury was attenuated by blocking the renin-angiotensin pathway and depended on ACE2 expression [12]. Thus, for SARS-CoV pathogenesis, ACE2 is not only the entry receptor of the virus but also protects from lung injury. We therefore previously suggested that in contrast to most other coronaviruses, SARS-CoV became highly lethal because the virus deregulates a lung protective pathway”

 

Going into a little bit more detail about the SARS COV2 residue 394 ( glutamine)on viral RBD and critical lysine 31 on ACE2 receptor,

The study emphasizes on the interaction  between  different residues of  viral  receptor binding domain and lysine residues of ACE 2 of both human and civet.

(.https://doi .org/10.1128/JVI.00127-20.)

(Yushun Wan,a Jian Shang,a Rachel Graham,b Ralph S. Baric,b Fang Lia)

“First, residue 493 in 2019-nCoV RBD (corresponding to residue 479 in SARS-CoV) is a glutamine (Fig. 1B and D). A previously designed SARS-CoV RBD is optimal for binding to human ACE2 (Fig. 1B and C)(26). According to the structure of this designed RBD, residue 479 is located near virus-binding hot spot Lys31 (i.e., hot spot 31) on human ACE2 (Fig. 1C). Hot spot 31 consists of a salt bridge between Lys31 and Glu35 buried in a hydrophobic environment. In civet SARS-CoV RBD (year 2002), residue 479 is a lysine, which imposes steric and electrostatic interference with hot spot 31. In human SARS-CoV RBD (year 2002), residue 479 becomes an asparagine. The K479N mutation removes the unfavorable interaction at the RBD-human ACE2 interface, enhances viral binding to human ACE2, and plays a critical role in the civet-to-human transmission of SARS-CoV (Fig. 1C)(24–26). Here, we constructed a structural model for the complex of 2019-nCoV RBD and human ACE2 (Fig. 1D). Importantly, Gln493 in 2019-nCoV RBD is compatible with hot spot 31, suggesting that 2019-nCoV is capable of recognizing human ACE2 and infecting human cells. Second, residue 501 in 2019-nCoV RBD (corresponding to residue 487 in SARS-CoV) is an asparagine (Fig. 1B and D). Based on our previous structural analysis, residue 487 in SARS-CoV is located near virus-binding hot spot Lys353 (i.e., hot spot 353) on human ACE2 (Fig. 1C)(26). Hot spot 353 consists of a salt bridge between Lys353 and Asp38 also buried in a hydrophobic environment. In civet SARS-CoV RBD (year 2002), residue 487 is a serine, which cannot provide favorable support for hot spot 353. In human SARS-CoV isolated in year 2002, residue 487 is a threonine, which strengthens the structural stability of hot spot 353. The S487T mutation adds the favorable interaction at the RBD-human ACE2 interface, enhances viral binding to human ACE2, and plays a critical role in the human-to-human transmission of SARS-CoV (24–26). In human SARS-CoV isolated in year 2003, residue 487 is a serine and there was no human-to human transmission for this SARS-CoV strain. “

 

 

INFERENCE

1. The viral RBD residues are primarily recognizing lysine residues on the ACE2 receptors.
2. There is involvement of breaking of salt bridges ( electrostatic and hydrogen bonds) between lysine residues and similar amino acids on the ACE 2 receptor.
3. It can be said that the RBD of viral sipke protein acts as lysine receptor.
4. The viral glutamine and asparagine residues are capable of breaking salt bridge bonds on the ACE2  receptor.

 

 

 

 

 

 

 

MECHANISM OF LYSINE ANALOUGES:

Lysine analogues such as Tranexemic acid , aminocaproic acid are antifibrinolytic agents.

Tranexamic acid is a synthetic derivative of the amino acid lysine and inhibits fibrinolysis by reversibly binding to lysine-binding sites on plasminogen, thereby preventing the cleavage of fibrin.

 

Now about the lysine residues on fibrin and binding of plasmin to the lysine residues:

. https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793(85)81150-9

 

“Plasmin catalysed hydrolysis of fibrinogen results primarily in the formation of fibrinogen fragments with C-terminal lysine residues, since plasmin preferentially cleaves Lys-Xaa bonds of fibrinogen”

 

“the Cterminal lysine residues of fibrinogen fragments are essential for high-affinity binding of the fragments to plasminogen, then any protein or peptide with C-terminal lysine residue may bind plasminogen and be a modulator of enzyme systems that involve plasminogen.”

 

 

OBSERVATION:

1. SIMILARITY OF THE CONTEXT OF MECHANISMS IN BOTH THE CASES

1. BOTH SYSTEM REQUIRES LYSINE BINDING (PLASMINOGEN AND VIRAL SPIKE PROTEIN)
2. BOTH  SYSTEM HAS SERINE PROTESE ASSISTNG THE MECHANISM ( UROKINASE  AND TMPRSS2 –TRANSMEMBRANE PROTEASE SERINE 2)(FOR REFERENCE-https://doi.org/10.1007/s00134-020-05985-9)
3. BOTH SYSTEM REQUIRES BREAKING OF EXISTING LYSINE RESIDUE BONDS ( PEPTIDE AND SALT BRIDGES RESPECTIVELY)

HENCE THEORITICALLY,  IT CAN BE OBSERVED THAT LYSINE ANALOUGES ( TRANEXEMIC ACID, AMINOCAPROIC ACID) WHO ARE PROVEN ANTI FIBRINOLYTICS, CAN BE PUT TO TEST TO CHECK THE EFFECTIVITY ON PREVENTING THE INTERACTION BETWEEN VIRAL SPIKE PROTEIN AND ACE2 RECEPTOR.

 

 

ACKNOWLEDGEMENT: REFERENCE:  1. https://doi.org/10.1007/s00134-020-05985-9

1. .https://doi .org/10.1128/JVI.00127-20.
2. . https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793(85)81150-9

 

opinions needed 

 

Zhang2020_Article_Angiotensin-convertingEnzyme2A.pdf

[Vmedvil2]

I am going to go with that you are a crank and have no idea what you are talking about, but I am not entirely sure but I am going with that you are what I call a "Coronavirus Crank".

Edited April 3, 2020 by VictorMedvil

[SAFFRONKNIGHT]

I am going to go with that you are a crank and have no idea what you are talking about, but I am not entirely sure but I am going with that you are what I call a "Coronavirus Crank".

[SAFFRONKNIGHT]

I can help you to understand, what I want to say ,

brother

Edited April 4, 2020 by SAFFRONKNIGHT

[SAFFRONKNIGHT]

You just need some basic concepts of medical sciences, biochemistry and pharmacology, to understand the concept dude

[Vmedvil2]

You just need some basic concepts of medical sciences, biochemistry and pharmacology, to understand the concept dude

No, I understand what you are saying the thing I don't understand is what a "Salt Bridge" is, which seems to be the target for the lysine, what do you mean by "Salt Bridge"?  Even if I knew what was meant by that I don't think that Lysine will damage this "Salt Bridge" which is why I am unsure but going on the side of you being a crank. This is the reason why, the glycoproteins of Herpes virus which cause cold sores is structurally different than COVID and SARS, like the earlier posts about Tea Tree oil preventing influenza glycoprotein binding then being a effective treatment for COVID which I also called as a crank treatment, I think they are structurally too different.

 

Herpes Virus Glycoprotein

 

COVID-19 Virus Glycoprotein

 

If you prove that, that "Salt Bridge" is present on the glycoproteins of both COVID and Herpes, I will believe and accept your claim is a possible treatment, however I want to see common nucleotide sequences at that location of lysine binding between the two before accepting the claim, I don't think they have similar nucleotide sequences however I could be wrong, until you prove that you are a crank.

Edited April 4, 2020 by VictorMedvil

[SAFFRONKNIGHT]

Thank you for your reply brother, i will definitely clarify.

 

I think there is some misunderstanding due to my way of writing and i am sorry for that.

 

1.SALT BRIDGE : it is a type of bond between the charged amino acids formed in a hydrophobic environment.

it consists of 2 components : 1. electrostatic interaction 2. hydrogen bond

 

 

This bond is very common in both organic and inorganic chemistry setting.

https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular)

 

2. You have misunderstood about the function and role of lysine.

 

Lysine is not going to break any salt bridges or bonds 

 

For better understanding i will divide it into 2 segments:

Segment 1(before the viral spike protein interaction) : According to the study (Yushun Wan,a Jian Shang,a Rachel Graham,b Ralph S. Baric,b Fang Lia)

 

The Lysine 31 and Lysine 353 residues on the ACE2 receptors ( which are both hot spots for viral spike protein interaction) exists normally by forming salt bridges with Glutamine 35 and Asparagine 38 respectively. ( which are also present on the ACE2)

 

 

Segment 2( during viral spike protein interaction ) : According to the same study, the viral spike protein ACE2 receptor binding domain (RBD), consist of several amino acid residues like residue 394, 493 ( both glutamine) , residue 487 (asparagine).

When there is interaction between Viral spike protein RBD and ACE2 receptors, the viral amino acid residues ( 394, 493 and 487) react with the residues on ACE 2 ( Lysine 31 and Lysine353 ) and manipulates(breaks)  their existing salt bridge bonds with Glutamine 35 and asparagine38 respectively and form new type of bond with the Viral residues (394, 493, 487). Hence initiating interaction.

Its is the Viral spike protein RBD residues which manipulates the salt bridges, not Lysine

 

This is why in the inference section, i wrote about, viral spike protein RBD acting as a lysine binding site or receptor ( for its affinity to lysine residues of ACE2).

 

3. Why Lysine Analouges.

 

First we need to understand the mechanism of lysine analouges like (Tranexemic acid, aminocaproic acid), which are potent anti fibrinolytics.

 

Mechanism:

 

First We need to understand, how breaking of fibrin clots takes place

1. it needs the activation of Plasminogen to Plasmin

for this it needs the help of enzymes like urokinase ( a serine protease)

 

to break fibrin clots, the enzyme plasminogen has to interact with lysine residues present on the fibrin, Plasminogen has lysine binding sites in 5 domains called krigle domains.

 

What lysine analouges like Tranexemic acid does???

 It simply prevents the interaction between lysine residues of fibrin and plasminogen by binding to the lysine binding sites of plasminogen. Compititive inhibition

( remember Tranexemic acid has structural similarity with lysine, that is why it is an analouge " synthetic lysine")

 

https://en.wikipedia.org/wiki/Tranexamic_acid

 

"Mode of action of aminocarboxylic acids The main action of the aminocaproic acid compounds is to compete with lysine binding sites on plasminogen and plasmin. They inhibit the activation of plasminogen by streptokinase, urokinase, and tissue activator. The binding of the heavy chain of plasmin to fibrin monomer is achieved by lysine binding sites. The blocking of these sites by aminocaproic acid causes stoichiometric inhibition of plasmin"

 

source:https://jcp.bmj.com/content/jclinpath/33/Suppl_14/35.full.pdf

 

 

 

Now as i have stated in the OBSERVATION section about the similarity of the two systems. i would want to share my hypothesis:

 

Probable mechanism of action: ( My hypothesis can be totally wrong)

If lysine analouges are used, then theoretically, there is a probability of  lysine analouges ( being structurally similar to lysine) intearcting with the Viral spike protein RBD residues (394,493,487 = which we know has affinity for lysine as per the studies).

If the lysine analouges are successful in  interacting with the RBD residues , the viral RBD is competitively inhibited from interacting with lysine residues of ACE 2 ( Lysine 31, and Lysine353), resulting in no interaction with ACE 2 and therefore no cell entry of the virus, and hence no replication.

 

 

This part is additonal :)

Moreover Lysine analouges are known to inhibit serine protease like Urokinase, which may also help in inhibiting  TMPRSS2 –TRANSMEMBRANE PROTEASE SERINE 2 ( found to be aiding viral spike protein RBD and ACE 2 membrane fusion)which is also a serine protease.

 

 

 

This is the assumption I have made, it may be totally wrong. But thanks for suggestons and replies.

 

Also thank you dude about the herpes glycoprotein and covid 19 glycoprotein information

[Vmedvil2]

Thank you for your reply brother, i will definitely clarify.

 

I think there is some misunderstanding due to my way of writing and i am sorry for that.

 

1.SALT BRIDGE : it is a type of bond between the charged amino acids formed in a hydrophobic environment.

it consists of 2 components : 1. electrostatic interaction 2. hydrogen bond

 

 

This bond is very common in both organic and inorganic chemistry setting.

https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular)

 

2. You have misunderstood about the function and role of lysine.

 

Lysine is not going to break any salt bridges or bonds 

 

For better understanding i will divide it into 2 segments:

Segment 1(before the viral spike protein interaction) : According to the study (Yushun Wan,a Jian Shang,a Rachel Graham,b Ralph S. Baric,b Fang Lia)

 

The Lysine 31 and Lysine 353 residues on the ACE2 receptors ( which are both hot spots for viral spike protein interaction) exists normally by forming salt bridges with Glutamine 35 and Asparagine 38 respectively. ( which are also present on the ACE2)

 

 

Segment 2( during viral spike protein interaction ) : According to the same study, the viral spike protein ACE2 receptor binding domain (RBD), consist of several amino acid residues like residue 394, 493 ( both glutamine) , residue 487 (asparagine).

When there is interaction between Viral spike protein RBD and ACE2 receptors, the viral amino acid residues ( 394, 493 and 487) react with the residues on ACE 2 ( Lysine 31 and Lysine353 ) and manipulates(breaks)  their existing salt bridge bonds with Glutamine 35 and asparagine38 respectively and form new type of bond with the Viral residues (394, 493, 487). Hence initiating interaction.

Its is the Viral spike protein RBD residues which manipulates the salt bridges, not Lysine

 

This is why in the inference section, i wrote about, viral spike protein RBD acting as a lysine binding site or receptor ( for its affinity to lysine residues of ACE2).

 

3. Why Lysine Analouges.

 

First we need to understand the mechanism of lysine analouges like (Tranexemic acid, aminocaproic acid), which are potent anti fibrinolytics.

 

Mechanism:

 

First We need to understand, how breaking of fibrin clots takes place

1. it needs the activation of Plasminogen to Plasmin

for this it needs the help of enzymes like urokinase ( a serine protease)

 

to break fibrin clots, the enzyme plasminogen has to interact with lysine residues present on the fibrin, Plasminogen has lysine binding sites in 5 domains called krigle domains.

 

What lysine analouges like Tranexemic acid does???

 It simply prevents the interaction between lysine residues of fibrin and plasminogen by binding to the lysine binding sites of plasminogen. Compititive inhibition

( remember Tranexemic acid has structural similarity with lysine, that is why it is an analouge " synthetic lysine")

 

https://en.wikipedia.org/wiki/Tranexamic_acid

 

"Mode of action of aminocarboxylic acids The main action of the aminocaproic acid compounds is to compete with lysine binding sites on plasminogen and plasmin. They inhibit the activation of plasminogen by streptokinase, urokinase, and tissue activator. The binding of the heavy chain of plasmin to fibrin monomer is achieved by lysine binding sites. The blocking of these sites by aminocaproic acid causes stoichiometric inhibition of plasmin"

 

source:https://jcp.bmj.com/content/jclinpath/33/Suppl_14/35.full.pdf

 

 

 

Now as i have stated in the OBSERVATION section about the similarity of the two systems. i would want to share my hypothesis:

 

Probable mechanism of action: ( My hypothesis can be totally wrong)

If lysine analouges are used, then theoretically, there is a probability of  lysine analouges ( being structurally similar to lysine) intearcting with the Viral spike protein RBD residues (394,493,487 = which we know has affinity for lysine as per the studies).

If the lysine analouges are successful in  interacting with the RBD residues , the viral RBD is competitively inhibited from interacting with lysine residues of ACE 2 ( Lysine 31, and Lysine353), resulting in no interaction with ACE 2 and therefore no cell entry of the virus, and hence no replication.

 

 

This part is additonal :)

Moreover Lysine analouges are known to inhibit serine protease like Urokinase, which may also help in inhibiting  TMPRSS2 –TRANSMEMBRANE PROTEASE SERINE 2 ( found to be aiding viral spike protein RBD and ACE 2 membrane fusion)which is also a serine protease.

 

 

 

This is the assumption I have made, it may be totally wrong. But thanks for suggestons and replies.

 

Also thank you dude about the herpes glycoprotein and covid 19 glycoprotein information

 

Physically Test it, it may inhibit COVID19 receptor binding, I expect a full lab report with the results.

Edited April 4, 2020 by VictorMedvil

[SAFFRONKNIGHT]

Brother I am a Doctor, and I do not have lab facilities.

I posted this on order to bring this idea to the people of science, and a potential lab employee, who might be interested to physically test it.

I have no problem with it.

It is just an idea, any body can borrow it, put to test, get results.

For the sake of humanity

[SAFFRONKNIGHT]

If you have some contacts, who can use this idea to bring results, please forward this idea to them.

[Vmedvil2]

If you have some contacts, who can use this idea to bring results, please forward this idea to them.

Contact these people, Link = https://www.lilly.com/contact-us

 

Link to independent clinical trials application page = https://www.lilly.com/clinical-research/clinical-trials

Edited April 4, 2020 by VictorMedvil

[SAFFRONKNIGHT]

Thank you very much brother

[Thoth101]

Brother I am a Doctor, and I do not have lab facilities.

I posted this on order to bring this idea to the people of science, and a potential lab employee, who might be interested to physically test it.

I have no problem with it.

It is just an idea, any body can borrow it, put to test, get results.

For the sake of humanity

Good luck trying to tell them anything. They don't want to take any suggestions because their heads are so far up their butts.

[SAFFRONKNIGHT]

Good luck trying to tell them anything. They don't want to take any suggestions because their heads are so far up their butts.

Ha ha true with maximum no. of people in this world

[Thoth101]

Ha ha true with maximum no. of people in this world

We could pretty much eradicate the virus with frequencies in a very short time. But I guess that would be to easy. There is agenda behind this which is why they won't take advice to other ways of doing it besides locking everyone down and locking everyone up.

[SAFFRONKNIGHT]

We could pretty much eradicate the virus with frequencies in a very short time. But I guess that would be to easy. There is agenda behind this which is why they won't take advice to other ways of doing it besides locking everyone down and locking everyone up.

What type of frequencies???

[Thoth101]

What type of frequencies???

For starters. I will have more on it but at work at the moment.

 

https://www.cia.gov/library/readingroom/document/cia-rdp96-00787r000500030001-5

 

A little snip of the document:

 

At this point the following question arose: If ultraviolet light is actually produced during cell division(mitosis), conversely can it--or light of another frequency--cause cells to divide? A.G Gurvich had said that this could occur.

This effect was recorded in the literature as "dark chemiluminescence" in ultraviolet, which sounds very simple. In fact, science has no more lifted the lid of the Pandora's box in which many possibilities and modification of living system by light defy discovery.