RAJDEEP

Ok, thank you The inference , content, and observation are my contribution. The pathogenesis and mechanism of lysine analouges are quoted from studies. Thank you for informing me

CAN LYSINE AND LYSINE ANALOUGES HAVE POTENTIAL ROLE IN PREVENTING VIRAL SPIKE PROTEIN AND ANGIOTENSIN CONVERTING ENZYME 2 (ACE2) ECTODOMAIN INTERACTION A 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 THEORETICALLY, IT CAN BE OBSERVED THAT LYSINE ANALOUGES ( TRANEXEMIC ACID, AMINOCAPROIC ACID) WHO ARE PROVEN ANTI FIBRINOLYTICS, CAN BE PUT TO TEST TO CHECK THE POTENTIAL ON PREVENTING THE INTERACTION BETWEEN VIRAL SPIKE PROTEIN AND ACE2 RECEPTOR. ACKNOWLEDGEMENT: REFERENCE: 1. https://doi.org/10.1007/s00134-020-05985-9 2. .https://doi .org/10.1128/JVI.00127-20. 3. . https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793(85)81150-9 PLEASE GIVE YOUR VALUABLE OPINION