Hou et al. proposed three different models for treating COVID-19 based on three different phenotypes which are found in different populations.  The following drugs were used in the models:

- hydroxychloroquine
- E-64D (a protease inhibitor)
- camostat mesylate (a TMPRSS2 inhibitor approved in Japan for treating chronic pancreatitis) 

These pharmacogenomic models have yet to be tested and validated.  

Michigan State University

There are existing drugs that could, in theory, based on their physiological roles, have a positive pharmacological effect on treating or preventing COVID-19.  These drugs may not have been tested yet, or they may have been proved to be ineffective.  

- ACE2 inhibitors
- serine protease inhibitors
- Mas receptor activators
- SARS-S and MERS-S inhibitors 
- soluble ACE2 receptors
- combination therapies
- N-acetylcysteine (NAC)
- antimicrobial peptides
- androgen receptors
- probiotics targeting the gut microbiota
- coronaviral protease inhibitors
- ACE inhibitors + Angiotensin Receptor Blockers (ARBs)
- JAK inhibitors
- Alpha-lipoic acid (ALA)
- Hydrogen Sulfide (H2S)

Theoretical COVID-19 Drug Targets and Candidates

Differences in COVID-19 inter-individual variability and lethality, along with differences among countries, raises the consideration of the role that predisposed genetics may play. Genetic variation may explain why some individuals without COVID-19 risk factors develop severe COVID-19.  Functional polymorphisms in the following genes are of interest due to their coded proteins' role in the pathogenesis of COVID-19:

- ACE2
- TMPRSS2

Understanding these variations in different populations could lead to more individualized treatment in COVID-19 patients.

Genetic Susceptibility to SARS-CoV-2 Infection in the Pathogenesis of COVID-19

Hou, Y., Zhao, J., Martin, W., Kallianpur, A., Chung, M. K., Jehi, L., ... & Cheng, F. (2020). New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Medicine, 18(1), 1-8.
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-020-01673-z

New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis

Four potential TMPRSS2 protease inhibitors were tested:

- Chemostat

- Upamostat

- Nafmostat

- Bromhexine hydrochloride

Each of these existing, clinically proven drugs were found to bind to the catalytic pocket of TMPRSS2 with high precision and specificity.  Theoretically, these drugs could impede SARS-CoV-2 S proteins from interacting with TMPRSS2 which would consequently influence infectivity.  This could be a hopeful target for antiviral drugs or a future vaccine.  

Using Serine Protease Inhibitors to Treat or Prevent COVID-19

It is hypothesized that a targeted Mas receptor, such as AVE0091, could prevent SARS-CoV-2 from entering cells with high ACE2 expression.  If so, this could lessen the morbidity and mortality of COVID-19.  

Using Mas Receptor Activators to Treat or Prevent COVID-19

At least 100 existing pharmaceuticals can theoretically bind to COVID-19's spike protein and hinder or slow the infection process. These include Irolapride, an antidepressant, and Pirifibrate, an antilipidemic. 
These existing drugs are valuable, as they are both readily available and may already be cleared for use in humans. Their effectiveness otherwise remains unknown. 

Using Existing Pharmaceuticals to Target Binding Pockets

In this study two SARS-CoV-2  inhibitors were identified and three compounds- cepharanthine, abemaciclib and trimipramine- were discovered to be broad-spectrum spike-mediated entry inhibitors. 
- spike protein: general information
- general procedure
- cepharanthine results
- abemaciclib results
- trimipramine results
- importance/Future Directions

Using SARS-S and MERS-S Inhibitors to Prevent COVID-19

Targeting the ACE2 receptor has been a recurring motif in pharmacological research of COVID-19, but most efforts have proven to be ineffective or dangerous to those who take these drugs.  One proposal is to create soluble "decoy" ACE2 receptors.  Theoretically, if the virus were to completely target these receptors, endogenous ACE2 receptors would remain unaffected.  This proposal also does not involve changing the expression of endogenous ACE2 which could have onerous outcomes.  Cell culture studies have shown that soluble ACE2 can reduce a viral infection by a factor of 5000.  This could be a useful therapeutic or prevention method.  

Using Soluble ACE2 Receptors to Treat or Prevent COVID-19

Hypothesized Combination Therapies to Treat COVID-19 Based on Pharmacogenomics

N-acetylcysteine (NAC) thins mucus as a mucolytic because of its its free sulfhydryl group which reduces disulfide bonds in mucus glycoproteins.  Additionally, it is a strong antioxidant.  NAC may be beneficial in treating or preventing SARS-CoV-2 infections in the following ways:

- NAC may be able to cleave SARS-CoV-2 E protein which would decrease its infectivity
- NAC has been shown to decrease angiotensin II bonds to angiotensin II type 1 receptors in vitro
- NAC has been shown to block ACE activity and limit the amount of Ang II both in vitro and clinically 
- NAC may be able to counteract the reactive oxygen species (ROS) produced by cytokine storm syndrome
- NAC has been shown to restore platelet GSH reserves and prevent protein glycosylation, a pathological mechanism of COVID-19 in diabetic patients
- NAC has been shown to inhibit NF-κB activation in an in vitro influenza (A and B) model which mediates COVID-19 pathology in the lungs by initiating the production of pro-inflammatory cytokines


Using N-acetylcysteine to Treat or Prevent COVID-19

Computational screening and molecular docking are two methods that are being used to discover new drugs to combat SARS-CoV-2 infections and COVID-19.  Many of these efforts to discover new drugs use SARS-CoV-2 S protein as a pharmacological target.  The concept of antimicrobial peptides is to introduce peptides to SARS-CoV-2 S protein that would change the viral protein's conformation so that it cannot properly interact with ACE2 receptors.  This would consequently stop the virus from infecting a cell.  These synthetic peptides would be more clinically favorable than other antivirals because they have no side effects, cause no hemolytic activity, and are not toxic to human cells.  The following peptides were tested by Souza et al.:

- Mo-CBP3-PepI
- Mo-CBP3-PepII
- Mo-CBP3-PepIII [22,23]
- RcAlb-PepI
- RcAlb-PepII
- RcAlb-PepIII [24]
- PepGAT
- PepKAA

Using Antimicrobial Peptides to Treat or Prevent COVID-19

TMPRSS2 is a serine protease involved in the cellular entry of SARS-CoV-2.  Its gene is regulated in part by upstream androgen receptors and has consequently been shown to be androgen-sensitive.  It may be possible to treat a SARS-CoV-2 infection using androgen deprivation therapy (ADT) or -anti-androgens which are currently used as prostate cancer therapies.  

Using Androgen Receptor Inhibitors to Treat or Prevent COVID-19

ACE2 inhibitors have been shown to have antiviral abilities against other CoVs, but their efficacy has yet to be tested for SARS-CoV-2.  Different ACE2 inhibitors have different functions, with some:

- targeting the ACE2 binding region so that SARS-CoV-2 S protein cannot bind there
- creating recombinant human ACE2 (rhACE2) that "tricks" the virus into binding to the recombinant ACE2 instead of somatic ACE2
- inhibiting the function of TMPRSS2, which would reduce the virus's ability to efficiently enter host cells

Targeting human proteases would be controversial, as there could be many adverse side effects.  Recently, the main SARS-CoV-2 protease structure was determined.  It is thought that an inhibitor to this viral protease could be created, and this could be a promising drug candidate.

Using ACE2 Inhibitors to Treat or Prevent COVID-19

The gut microbiota is thought to be  an important regulator of antiviral immune responses.  Studies have shown that modulating the gut microbiota has been able to reduce viral-related enteritis, severe pneumonia cases requiring ventilator assistance, and the spread of influenza in lung epithelial cells.  It is thought that probiotic treatment in COVID-19 patients could promote a healthy gut microecology, which could mitigate GI symptoms, as well as protect the respiratory system from other infections via the bi-directional communication network that is thought to exist between the gut and lung microbiotas.  

Using Probiotics to Treat or Prevent COVID-19

Figure 1
- People who develop ALI/ARDS along with COVID-19 end up with an infected lung
- Eventually, inflammation in organ tissues will develop due to elevated IL-6 levels and decreased white blood cells; oxidation stress occurs
- Administering melatonin into the system could lead to recovery, as it can lower IL-6 levels and the effect of oxidative enzymes is decreased
- If melatonin does not work, the body’s immune system will go out of control (cytokine storm)
- Administering melatonin once again can help prevent problems associated with ALI/ARDS


Using Melatonin to Treat or Prevent COVID-19

JAK inhibitors are usually used to help people who may be affected by rheumatism, which is an autoimmune disease. They are known as DMARDs. People who have rheumatism, their medications usually consist of immunosuppressants which cause a higher infectious risk, leading to concerns of several diseases. Interestingly, people who are taking medications with JAK inhibitors are not experiencing this issue with COVID-19. No data suggests that patients with rheumatic diseases are at an increased risk for COVID-19 compared to the general population. Medications such as Baricitinib and Xeljanz (generic name Tofacitinib) which have JAK inhibitors in them are, predicted to block SARS-CoV-2 receptor-mediated endocytosis into pulmonary epithelial cells. An open-label study with 12 patients with oral baricitinib added to ritonavir/lopinavir therapy showed promising results as all patients improved at 2 weeks and required no ICU admission.


Using JAK Inibitors to Treat or Prevent COVID-19

Alpha-lipoic acid (ALA) is a drug that is currently used to treat diabetic polyneuropathy.  It increases insulin signalling sensitivity, functions as an antioxidant, and inhibits NF-kB activity.  Additionally, ALA has been demonstrated to have anti-viral properties.  Its ability to reduce NF-kB activity, increase intracellular glutathione concentrations, chelating metal ions, and restoring antioxidant levels have all been shown to have protective effects against different viruses.  ALA may be specifically useful in treating or preventing COVID-19 because of its ability to prevent ACE2 upregulation by inhibiting ADAM17, increasing intracellular pH by activating sodium/potassium pumps, and increasing the amount of intracellular antioxidants to bolster the host cell's defense mechanism.  

Using Alpha-Lipoic Acid (ALA) to Treat or Prevent COVID-19

Coronavirus 3C-like proteases are the enzymes on the virus that play a key role in viral replication. Coronaviral protease inhibitors could theoretically prevent the virus from initially infecting the host cell, and appear to be promising drug targets. 

Types:
- GC376
- C-Phycoyanin
- peptidomimetic α-ketoamides 

Using Coronaviral Protease Inhibitors to Treat or Prevent COVID-19

Schuler et al. demonstrated using both mouse and human cell lines that TMPRSS2 expression increased with age.  The regulation of the enzyme during development could contribute to why infants and children are less susceptible to severe COVID-19.  Hou et al. writes that is will be important to study age-related polymorphisms of TMPRSS2 in the future using genetic epidemiology methods.

Age-Related Polymorphisms of TMPRSS2

Because the incidence and mortality rates of COVID-19 are significantly different in different regions of the world, it is thought that human variation may play a greater role than viral variation in determining these outcomes.  Significant variation in the gene TMPRSS2, which codes for the protease TMPRSS2, has been observed in different ethnic groups.  This may contribute to the different rates of infectivity seen in different populations.  

Genetic variation within the TMPRSS2 protease may play a role in COVID-19 infection

This graphic shows the distribution of 61 potentially harmful ACE2 polymorphisms by population using variant assembly of databases, annotation of non-synonymous polymorphisms, and predictive-deleterious scoring. 
- databases: Genome Aggregation Database, Exome Sequencing Project, and 1000 Genomes Project (1KGP, www.internationalgenome.org)
- non-synonymous variant annotation: ANNOVAR
- deleterious assessment: CADD and Polyphen2 

The top bar shows ACE2 functional domains, and the vertical notches represents population counts of the respective variant. The heat map depicts polymorphism frequencies found within the different populations.

- 39% of variations occur in African/African-American (AFR) populations
- 54% of variations occur in non-Finnish European (EUR) populations
- Amish (AMI) and Ashkenazi Jewish (ASJ) populations do not appear to have any of these polymorphisms
- variants such as p.Arg514Gly may influence COVID-19 pathogenesis and its associated cardiovascular conditions by altering the AGT-ACE2 pathway

Population group legend: AFR, African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish European; SAS, South Asian; PNA, population not assigned

Nonsynonymous ACE2 Variations by Population

This graphic shows the distribution of 63 potentially harmful TMPRSS2 polymorphisms by population using variant assembly of databases, annotation of non-synonymous polymorphisms, and predictive-deleterious scoring.

- databases: Genome Aggregation Database, Exome Sequencing Project, and 1000 Genomes Project (1KGP, www.internationalgenome.org)
- non-synonymous variant annotation: ANNOVAR
- deleterious assessment: CADD and Polyphen2

The top bar shows TMPRSS2 functional domains, and the vertical notches represents population counts of the respective variant. The heat map depicts polymorphism frequencies found within the different populations.

- 35% of variations occur in African/African-American (AFR) populations
- 59% of variations occur in non-Finnish European (EUR) populations
- all populations carry p.Val160Met (~25% allele frequency)
- p.Asp435Tyr, which codes for a key residue for the substrate binding of TMPRSS2, is only carried by non-Finnish European (EUR) populations
- if TMPRSS2 polymorphisms cause gene overexpression, Down Syndrome may be a risk-factor for COVID-19 due to TMPRSS2's localization on chromosome 21.

Population group legend: AFR, African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish European; SAS, South Asian; PNA, population not assigned

Nonsynonymous TMPRSS2 Variations by Population

Allelic variants in the ACE2 gene has been observed in different ethinic populations, as well as in case-control studies within ethnic groups. However, these are present in relatively low frequencies. Functional studies are encouraged to characterize the relationship between ACE2 variants and COVID-19 severity, but no causal relationship can be made to date.

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