Efficacy of Sunlight Activated Synthetic Porphyrin in COVID-19 Infected Patients
Efficacy of Sunlight Activated Synthetic Porphyrin in COVID-19 Infected Patients
Efficacy of Sunlight Activated Synthetic Porphyrin in COVID-19 Infected Patients (SnPPIX)

 Mahmoud ELkazzaz(1),Rokia yousry abdelaziz sallam(2)

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 Abstract :

 The novel coronavirus pneumonia (COVID-19) is an infectious acute respiratory caused by the
 novel coronavirus. The virus is a positive-strand RNA virus with high homology to bat
 coronavirus. Depending on published study in which , conserved domain analysis, homology
 modeling, and molecular docking were used to compare the biological roles of specific
 proteins of the novel coronavirus. The principal investigator demonstrated according to
 previous researches that some viral structural and nonstructural proteins could bind to the
 porphyrin, respectively. At the same time, orf1ab, ORF10 and ORF3a proteins coordinated to
 attack heme on the 1-beta chain of hemoglobin, COVID-19 binds to the porphyrin of haem and
 displaces iron and a study denonestrated that Covid-19 could cause acquired acute porphyria
 which is the condition in which there is excess accumulation of porphyrin intermediate
 metabolites. This point can be taken advantage of X-ray induced visible luminescence of
 porphyrin for producing of Reactive Oxygen Species (ROS).Many porphyrins are benign in the
 dark but are transformed by sunlight into caustic, flesh-eating toxins Porphyrins have been
 used for photodynamic therapy (PDT) against a wide range of targets like bacteria, viruses
 and tumor cells It has been reported that ROS-based inactivation of viruses may occur due to
 several reasons, such as protein oxidation, single strand breaks in the RNA genome and
 protein-RNA crosslinking. Since ROS-based inactivation has a multi-targeted mechanism, it is
 much less likely that a virus would be able to develop resistance against it. Recently,
 porphyrins, already in use as photosensitizers for Photodynamic Therapy (PDT), were a study
 target to applications in medical area, namely as possible contrast agents in MRI. could be
 observed some examples of porphyrin derivatives already study as MRI contrast media. Low dark
 toxicity, neoplastic tissue affinity and synthetic accessibility are some of the important
 properties that contribute for its selection. In MRI studies was found that CM based on
 paramagnetic metalloporphyrins showed higher affinity for neoplastic tissues, observed by
 increased relaxation time of the neoplastic tissues, which is reflected on an increase in MRI
 signal and consequently in a better neoplastic lesions detection. A study demonestrated that
 The sulfonated tetranaphthyl porphyrin contrast agents in MRI (TNapPS), sulfonated
 tetra-anthracenyl porphyrin (TAnthPS), and sulfonated 2,6-difluoro-meso-tetraphenylporphine
 [TPP(2,6-F2)S] and its copper chelate [TPP(2,6-F2)S,Cu], which reduced HIV infection by 99,
 96, 94, and 96%, respectively. Previous studies which showed that Covid -19 binds to the
 porphyrin of haem and displaces iron in addition to Sulfonated porphyrins and
 light-stimulated Sn- protoporphyrin IX have broad antiviral activity against more distinct
 types of viruses, Co-protoporphyrin IX and Sn-protoporphyrin IX inactivate Zika, Chikungunya
 and other arboviruses by targeting the viral envelope Porphyrins are amphipathic molecules
 able to interact with membranes and absorb light, being widely used in photodynamic therapy.
 Previously, we showed that heme, Co-protoporphyrin IX (CoPPIX) and Sn-protoporphyrin IX
 (SnPPIX) directly inactivate DENV and YFV infectious particles. Here we demonstrate that the
 antiviral activity of these porphyrins can be broadened to CHIKV, ZIKV, Mayaro virus, Sindb
 is virus and Vesicular Stomatitis virus. Porphyrin treatment causes viral envelope protein
 loss, affecting viral morphology, adsorption and entry into target cells , Finally, the
 principal investigator expect that viral load will be declined with sunlight because In
 particular, porphyrins absorb essentially all the UV/visible light wavelengths in the
 emission spectrum of the sun; hence they are active at very low doses .

 Keywords: COVID 2019 ,Infection, Sulfonated porphyrins and X-ray induced visible luminescence
 of porphyrin
Efficacy of Sunlight Activated Synthetic Porphyrin in COVID-19 Infected Patients (SnPPIX)

 Official Title: Efficacy of Based MRI Contrast Media Against Covid-19

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 Introduction:

 Pandemic Covid-19 pneumonia, of SARS-CoV-2 aetiology, presents an existential threat to
 health care systems globally. Multiple therapeutic and prophylactic agents are currently
 undergoing clinical trial, including 23 clinical trials of (hydroxy) chloroquine in China.
 While progress towards a curative agent or vaccine is promising, the principal limiting
 factor in public health emergency is time, and therefore Virus resistance to antiviral
 therapies is an increasing concern that makes the development of broad-spectrum antiviral
 drugs urgent. Targeting of the viral envelope, a component shared by a large number of
 viruses, emerges as a promising strategy to overcome this problem. Natural and synthetic
 porphyrins are good candidates for antiviral development due to their relative hydrophobicity
 and pro-oxidant character a pre-existing licensed therapeutic would offer reprieve to health
 care systems operating at the edge of capacity. In this brief communication, the Principal
 investigator argues that Covid-19 has high probability of being more than a disease of
 pneumonia, and that critical Covid-19 patients may be experiencing a form of acquired acute
 porphyria. Readily available interventions exist to treat acute porphyria and the position is
 advanced that urinalysis of critical Covid-19 patients would diagnose this pathology.

 COVID-19 binds to porphyrin and cause acquired porphyria.

 Erythrocytes are strongly implicated in the pathophysiology of Covid-19. Wuhan University
 researchers argue that the role of erythrocytes in the pathophysiology of Covid-19 is
 under-estimated; the co-efficient of variation of red blood cell distribution width (RDW) is
 predictive of severity of disease state (Gong 2020). Elevated RDW is correlated with reduced
 erythrocyte turnover; red blood cells become smaller as they age and the delay in clearance
 expands the low-volume tail of the volume distribution (Patel 2015). Suppressed erythrocyte
 turnover may indicate erythropoietic distress and function as a compensatory mechanism to
 maintain circulating red blood cell levels (Patel 2015).

 Excess porphyrins in red blood cells can precipitate cell lysis and development of hemolytic
 anaemia (Sassa 2006). Macaques infected with SARS-CoV- 2 also have decreased red blood cell
 numbers (Munster 2020) and susceptibility to SARS-CoV-2 appears to be determined by blood
 group; blood group A is most affected whereas blood group O seems to be protected (Yang
 2020). This finding is concordant with previous studies showing that susceptibility to the
 2003 strain of SARS-CoV was determined by blood group (Guillon 2008). Preliminary evidence
 suggests that CD147, the determinant of the Ok blood group system, binds the spike protein of
 SARS-CoV-2 (Wang 2020). Incidentally, CD147 functions as an essential receptor for
 erythrocyte invasion by Plasmodium falciparum (Crosnier 2011). Blockade of CD147 abrogates
 the normal recirculation of erythrocytes, from the spleen into the general circulation,
 leading to selective trapping of red blood cells in the spleen as development of a form of
 anaemia (Coste 2001). Autopsy of deceased Covid-19 patients reveals that the spleen is
 significantly reduced in size. Reduction in spleen size would be expected in the event that
 the spleen has emptied its reserve of erythrocytes into the circulation as part of a normal
 physiological response to anaemia (Dale 2016).

 Primate models of Covid-19 (Munster 2020) and human Covid-19 patients have subnormal
 haemoglobin levels (Chen 2020). Clinical evaluation of almost 100 Wuhan patients reveals
 haemoglobin levels below the normal range in most patients as well as increased total
 bilirubin and elevated serum ferritin (Chen 2020). Hyperbilirubinemia is observed in acute
 porphyria (Sassa 2006) and would be consistent with ineffective erythropoiesis (Sulovska
 2016) and rapid haemoglobin turnover.

 COVID-19 and Porphyrin of haem:-

 Elevated serum ferritin levels are typical of acute porphyria (Trier 2013) and would be
 expected upon dissociation of iron from haem. A mechanism by which SARS-CoV-2 might attack
 the 1beta chain of haemoglobin has been proposed; the product of open reading frame 8 (ORF8)
 binds to the porphyrin of haem and displaces iron, according to bioinformatics prediction
 analyses (Liu 2020).

 The oxygen-carrying capacity of erythrocytes would therefore be compromised by SARS-CoV-2,
 thereby exacerbating the difficulties already experienced by the patient, in terms of
 maintaining partial pressure of oxygen in the alveoli (PaO2). While the impact of SARS-CoV-2
 targeting of haemoglobin on oxygen content of the blood would therefore be considerable, the
 author proposes that perhaps of greater concern, are potential ramifications upon homeostatic
 regulation of haem anabolism. Haem biosynthesis is exquisitely controlled by seven
 enzyme-controlled reactions proceeding from the first intermediate, aminolevulinic acid
 (ALA), to haem as thefinal product. Haem negatively regulates the first step in the pathway
 by repressing expression of aminolevulinic acid synthase (ALAS).

 SARSCoV- 2 is predicted to directly interfere with haem production (Liu 2020), and this
 prediction is supported by empirical evidence of reduced haemoglobin levels in Covid-19
 patients (Chen 2020) and in animal models of the disease (Munster 2020). Decreased haem
 production dampens repression of ALAS, and thereby increases the production of haem
 precursors, leading to accumulation of porphyrin intermediate metabolites. All of the haem
 pathway intermediates are potentially toxic (Sassa 2006). During an attack of acute
 porphyria, ALAS is induced 2006) and this perturbation continues until sufficient haem
 synthesis is restored. Phenotype of SARS-CoV-2 porphyrin excess is hypothesised to mimic
 extreme lead poisoning; both as examples of acquired acute porphyria.

 Overproduction of haem precursors - aminolevulinic acid (ALA) and porphobilinogen (PBG), in
 particular - manifests life-threatening attacks (Pischik 2015) with neurovisceral symptoms
 (Sassa 2006), including: abdominal pain (85-95% cases), vomiting (43-88%), constipation
 (48-84%), muscle weakness (42-60%), mental symptoms (40-58%), pain of the limbs, head, neck
 and chest (50-52%), hypertension (36-54%), tachycardia (28-80%), convulsion (10-20%), sensory
 loss (9-38%), fever (9-37%), respiratory paralysis (5-12%) and diarrhoea (5-12%).
 Neurotoxicity of aminolevulinic acid accounts for the plethora of neurovisceral symptoms and,
 interestingly, there is considerable overlap between neurovisceral complaints of ALA excess
 and extra-pulmonary symptoms of critical Covid-19 patients. Extra-pulmonary symptoms of
 Covid-19 are significant but under-estimated, including gastrointestinal symptoms (Poggiali
 2020), which news reports suggest may affect in the region of 50% Covid-19 patients.
 Neurological problems also appear to be overlooked by the hyper-focus on respiratory symptoms
 (Zhao 2020). Of 214 Covid-19 patients, 36.4% experienced neurological manifestations
 including: headache, dizziness, acute cerebrovascular incidents and impaired consciousness
 (Mao 2020). Loss of autonomic control of breathing has also been reported and autonomic
 neuropathy is a clinical feature of acute porphyria (Laiwah 1985). Neuropsychiatric symptoms
 of Covid-19 may be downstream of irregularities in haem metabolism.

 The most important question is now asked by Principal investigator Can Sunlight stimulated
 porphyrins act against COVID-19 as like as Sn- protoporphyrin IX mechanism in impeding the
 entry and division of the virus(Zika, Chikungunya and other arbo viruses) by targeting the
 viral envelope and protect hemoglobin and blood components that are affected by the viral
 infection?

 The principal investigator expect the possibility of inhibiting Covid -19 by Sulfonated
 porphyrins X-ray induced visible luminescence of porphyrin and light-stimulated Sn-
 protoporphyrin IX because According to previous studies which showed that Covid -19 binds to
 the porphyrin of haem and displaces iron in addition to Sulfonated porphyrins and
 light-stimulated Sn- protoporphyrin IX have broad antiviral activity against more distinct
 types of viruses, Co-protoporphyrin IX and Sn-protoporphyrin IX inactivate Zika, Chikungunya
 and other arboviruses by targeting the viral envelope Porphyrins are amphipathic molecules
 able to interact with membranes and absorb light, being widely used in photodynamic therapy.
 Previously, we showed that heme, Co-protoporphyrin IX (CoPPIX) and Sn-protoporphyrin IX
 (SnPPIX) directly inactivate DENV and YFV infectious particles. Here we demonstrate that the
 antiviral activity of these porphyrins can be broadened to CHIKV, ZIKV, Mayaro virus, Sindb
 is virus and Vesicular Stomatitis virus. Porphyrin treatment causes viral envelope protein
 loss, affecting viral morphology, adsorption and entry into target cells (Neris 2018)

 The sulfonated tetranaphthyl porphyrin (TNapPS), sulfonated tetra-anthracenyl porphyrin
 (TAnthPS), and sulfonated 2,6-difluoro-meso-tetraphenylporphine [TPP(2,6-F2)S] and its copper
 chelate [TPP(2,6-F2)S,Cu], which reduced HIV infection by 99, 96, 94, and 96%, respectively
 (Andrei 2002)

 Treatment of HepG2 cells with heme, CoPPIX and SnPPIX after DENV infection reduced infectious
 particles without affecting viral RNA contents in infected cells. The reduction of viral load
 occurs only with the direct contact of DENV with porphyrins, suggesting a direct effect on
 viral particles. Previously incubation of DENV and YFV with heme, CoPPIX and SnPPIX resulted
 in viral particles inactivation in a dose-dependent manner. Biliverdin, a noncyclical
 porphyrin, was unable to inactivate the viruses tested. Infection of HepG2 cells with
 porphyrin-pretreated DENV2 results in a reduced or abolished viral protein synthesis, RNA
 replication and cell death. Treatment of HepG2 or THP-1 cell lineage with heme or CoPPIX
 after DENV infection with a very low MOI resulted in a decreased DENV replication and
 protection from death. (Assunção 2016)

 In summary, SARS-CoV-2 would not be the first known virus to alter porphyrin metabolism;
 hepatitis C virus (Hep C) and human immunodeficiency virus(HIV) infection lead to a non-acute
 form of porphyria (Blauvelt 1996). So the principal investigator expects and suggests that
 porphyrin based therapy is suitable and effective treatment against COVID-19 and could
 Protects hemoglobin and RBCs from dangerous influence of COVID-19 .The possibility of
 therapeutic application of porphyrins or their use as models to design new antiviral drugs
 against DENV ,COVID -19 and YFV.
Inclusion Criteria:

 Adult SARI patients with 2019-ncov infection confirmed by PCR; Absolute value of
 lymphocytes < 0. 6x 109/L; Severe respiratory failure within 48 hours and requires
 admission to ICU. (severe respiratory failure was defined as PaO2/FiO2 < 200 mmHg and was
 supported by positive pressure mechanical ventilation (including non-invasive and invasive
 mechanical ventilation, PEEP>=5cmH2O))

 Exclusion Criteria:

 -  History of malignancy except carcinoma in situ in the cervix, early stage prostate
 cancer or non-melanoma skin cancers. Cancer free for less than 5 years.

 -  Use of investigational drugs or participation in another clinical trial within 30 days
 or 5 half-lives prior to screening, whichever is longer.

 -  Serum ferritin > 500 ng/ml or who have received IV iron within 28 days of screening,
 or currently being treated with oral iron.

 -  Women who are pregnant, breastfeeding, or planning to become pregnant while
 participating in the study.

 -  Regular use of drugs of abuse and/or positive findings on urinary drug screening.

 -  Subjects who are severely physically or mentally incapacitated and who, in the opinion
 of investigator, are unable to perform the subjects' tasks associated with the
 protocol.

 -  Presence of any condition which, in the opinion of the investigator, places the
 subject at undue risk or potentially jeopardizes the quality of the data to be
 generated.

 -  Subjects with history of photosensitivity or active skin disease, which, in the
 opinion of the investigator could increase the risk of photosensitivity.

 -  Subjects with abnormal baseline liver tests or hepatitis serologies that suggest
 active infection.

 -  Liver disease

 -  Renal disease

 -  Known hypersensitivity or previous anaphylaxis to SnPP and Sulfonated porphyrins