Covid-19 brings thoughts on the development of broad-spectrum antiviral drugs
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Covid-19 brings thoughts on the development of broad-spectrum antiviral drugs
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Covid-19 brings thoughts on the development of broad-spectrum antiviral drugs
Background of broad-spectrum antiviral drug development
The global outbreak of Covid-19 has exposed the huge flaws and loopholes in human public health.
For pharmaceutical organizations, the timely development of targeted antiviral drugs has become a central element of the storm.
Although vaccines and antiviral drugs have been achieved at a speed that completely exceeds conventional standards, the world has still become a playground for the raging virus, but it has brought extremely painful losses to human beings. A large number of patients lost their lives due to lack of timely and effective treatment. life.
Although the storm has not subsided, the pharmaceutical industry has begun to reflect on the challenges brought to mankind, one of which is the development of broad-spectrum antivirals (BSA, broad-spectrum antivirals) .
We know that there are many broad -spectrum antibiotics on the market . The so-called broad-spectrum antibiotics are antibiotics that act on the two major bacterial groups of Gram-positive bacteria and Gram-negative bacteria at the same time, [1] or any antibiotics that act on a variety of pathogenic bacteria.
[2] These broad-spectrum antibiotic agents can often be used to stabilize the condition when a bacterial infection is suspected but the bacterial population is unknown (also known as empiric therapy) , or when multiple groups of bacteria are suspected.
Especially for life-threatening infections, targeted treatment cannot wait until the pathogen is identified, and the role of broad-spectrum antibiotics is irreplaceable in this case.
Broad-spectrum antibiotics are in contrast to those narrow -spectrum antibiotics that are effective against specific groups of bacteria . [3]
An example of a commonly used broad-spectrum antibiotic is ampicillin (also known as ampicillin, Figure 1) . Ampicillin is a beta-lactam antibiotic that treats a variety of bacterial infections. [4] Indications include respiratory tract infection, urinary tract infection, meningitis, salmonella infection, and endocarditis.
In addition to ampicillin, common broad-spectrum antibiotic drugs include doxycycline, minocycline, aminoglycosides (except streptomycin) , amoxicillin/clavulanic acid (Augmentin) , azithromycin, carbapenems (such as imipenem) , piperacillin/tazobactam, quinolones (such as ciprofloxacin) , tetracyclines (except sarecycline) , chloramphenicol, ticarcillin, trimethoprim/ Sulfamethoxazole (Bactrim) , and many other types.
Figure 1. Ampicillin chemical structure
Compared with the blooming of broad-spectrum antibiotics everywhere, the development of broad-spectrum antiviral drug BSA is obviously lagging behind.
Although there are many potential broad-spectrum antiviral drugs in various clinical stages, few true broad-spectrum antiviral drugs are currently being used effectively.
Broad-spectrum antivirals (BSAs) in concept are drugs that inhibit the replication of multiple viruses (viruses belonging to two or more virus families) .
BSA works by inhibiting viral proteins such as polymerases and proteases , or by targeting host cell factors that are utilized by the virus during infection and replication. [5]
As of 2021, there are 150 known BSAs in various stages of development that are effective against 78 human viruses. [6] BSA is a potential candidate for treatment of emerging as well as re-emerging viruses such as Ebola, Marburg, and SARS-CoV-2. [7] Many BSAs have shown antiviral activity against other viruses than those originally studied, such as remdesivir and interferon alpha .
Necessity and challenges of broad-spectrum antiviral drug development
One factor contributing to the lack of broad-spectrum antiviral drugs is the lag in virus detection technology, especially for respiratory viruses.
Routine tests for influenza and respiratory syncytial virus (RSV) were developed today because these infections are known to hospitalize thousands of patients worldwide and can be treated.
But until recently, tests for the widespread detection of other viruses were not available or used routinely.
This delay has led to a vicious cycle: without the right tests, the extent of severe disease caused by the virus is unknown; and the lack of knowledge of the severity of the virus’s disease-causing severity has created an impetus for viral diagnostics and the development of antiviral drugs. cannot be mobilized. Although testing technology is improving, testing is still not widely available.
Even with testing, many viral pathogens cannot be treated. This is exactly what happened in the early days of the COVID-19 pandemic: We know very little about the virus that causes it, and there are no treatments for the infection.
Although SARS-CoV-2 is the seventh coronavirus known to infect humans, humans are still not up to the challenge quickly enough.
Although effective COVID-19 management requires antiviral and anti-inflammatory therapeutic strategies, in the face of crisis, people need an effective, safe and rapid ( this rapid criterion is particularly important here) antiviral drugs for treatment and prevention.
However, given that drug development takes an average of 12 years from target discovery to approval, it is unrealistic to expect safe and selective antiviral drugs to be developed in such a short period of time.
Just imagine that if rationally developed, effective broad-spectrum antiviral drugs exist, they have the potential to alter the global response to SARS-CoV-2 and significantly reduce the impact of the pandemic on the safety of human life and the global economy.
If we look at the COVID-19 epidemic from a positive perspective, it at least prompts people to reflect and improve the development of broad-spectrum antiviral drugs, which can be viewed from two aspects. [8]
First, the COVID-19 pandemic has raised awareness of the lethality of viruses: a variety of respiratory viruses besides influenza and RSV, including coronaviruses, human metapneumovirus (HMPV), parainfluenza viruses, and even common cold viruses ( nasal viruses) , may lead to serious diseases and high hospitalization rates, and even seriously threaten the lives of patients.
This stimulates a “virtuous cycle”: the more we test, the more viruses we find that cause severe disease, and the more we recognize the need to develop new therapeutic strategies to combat them.
Second, recent outbreaks caused by novel viruses such as avian influenza A (H3N2, 1968) , swine influenza (H1N1, 2009), and the COVID-19 coronavirus (SARS-CoV-2, 2019) have highlighted the need for Broad-spectrum antiviral drugs for pandemic preparedness.
Like the SARS and MERS coronaviruses, these pandemic viruses are zoonotic: they spread from nonhuman animal hosts, sometimes through intermediate hosts.
This means that they pose a serious threat to human health, especially when viruses such as SARS-CoV-2 are well suited for human-to-human transmission because human hosts lack specific immunity to these emerging pathogens.
In the face of this dilemma, the development of broad-spectrum antiviral drugs is the key weapon to suppress the rapid and uncontrolled spread of the virus.
Broad-spectrum antiviral drug development ideas [9]
Most approved antiviral drugs target viral proteins, often acting selectively against one virus.
For example, the antiviral active peptide nirmatrelvir in Paxlovid targets the 3C-like protease (3C-like protease, or main protease, abbreviated as 3CL Pro or M Pro ) of the SARS-CoV-2 virus .
Historically, antiviral drug development has been disproportionately focused on targeting viral proteins, supporting the development of ” direct-acting antivirals” (DAAs, direct-acting antivirals) .
However, in addition to directly targeting viral protein receptors, we also know that viruses utilize a large number of host cell proteins (host proteins) to perform important steps in their life cycle.
Targeted antiviral agents ” (HDAs, host-directed antiviral agents) . Since viruses from one family often use the same host cell proteins, targeting these proteins could lead to drugs with broad-spectrum antiviral activity and create barriers to viral drug resistance.
A key feature of HDAs is that their development can take place before outbreaks of viral pathogens .
The need for HDA is underscored by the fact that more than a dozen zoonotic viruses have caused deadly human disease in recent years and may still be potential sources of future outbreaks.
Host protease inhibitors that block viral entry
Respiratory viruses, such as influenza, parainfluenza, and coronavirus, rely on host proteases to activate their entry factors , which facilitate membrane fusion and entry into airway epithelial cells.
Transmembrane protease serine 2 (TMPRSS2, transmembrane protease serine 2) is a ubiquitously expressed serine protease that cleaves and activates the hemagglutinin (HA, hemagglutinin) of human influenza virus and the spike S protein of SARS-like coronavirus to important. [ 10]
TMPRSS2 is dispensable for host development and homeostasis and thus may constitute an attractive therapeutic target. [11]
It should be noted that the host proteins targeted by HDA should be those that do not play a key role in the host cell itself, so their inhibition will not have adverse effects or safety issues. This is the development of HDA. prerequisites.
Figure 2. Camostat chemical structure
Camostat (Figure 2) is a clinical-stage serine protease inhibitor capable of blocking viral entry of SARS-CoV-2 and influenza viruses. [9]
Serine proteases involved in the pathogenesis of respiratory viruses are classified as trypsin -like proteases with structurally conserved active sites. This property of trypsin-like proteases can be used to design inhibitors with broad-spectrum activity. [12]
Although camostat inhibited the entry and replication of SARS-CoV-2, it did not completely abolish viral replication, which may reflect that the way the S protein is activated may not be achieved through a single pathway.
In addition to TMPRSS2, the host cell’s furin also plays a key role in cutting the virus in the process of invading the host, so it can also provide ideas for the development of HDAs.
Furin-mediated cleavage can act on several viral glycoproteins from different virus families, including Borna-, Bunya-, Corona-, Filo-, Flavi-, Herpes-, Orthomyxo-, Paramyxo-, Pneumo-, Retro- and Toga virus. [13]
Induced interferon antiviral [8]
HDAs can also be developed by enhancing the patient’s own immune response to viral infection.
This strategy can not only avoid viral drug resistance, but also provides the possibility for the development of broad-spectrum antiviral drugs.
This is because they trigger the body’s natural defenses against any virus, regardless of its identity, mutation status or drug resistance.
Therefore, this host-targeted antiviral drug holds the greatest promise as a broad-spectrum antiviral drug.
Interferon (IFN, Interferons) is a class of signaling proteins secreted by various cell types to coordinate the body’s natural antiviral response.
Type I interferon in the interferon family, as part of the innate immune response, constitutes the body’s first line of defense against viruses, including multiple IFNα and IFNβ subtypes, and four type III IFNλ subtypes.
Innate immunity is an instinctive response of the human body to infection, which is spontaneous and non-specific to infectious pathogens.
In infected cells, IFNβ and IFNα subtypes initiate an immediate and strong response to coordinate the antiviral response; at the same time, they also initiate pathways in uninfected cells to prevent viral replication, produce antibodies against the virus and T cells Adaptive immune response and activation of immunomodulatory pathways.
Because type I interferon receptors are widely expressed throughout the body, they protect many different types of cells from viruses.
IFNβ is more responsive than IFNα to most respiratory viruses. IFNλ acts similarly, but its receptors are predominantly expressed on epithelial cells, thus limiting its protective effects on other cells.
Injections of IFNβ and IFNα have been approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS, multiple sclerosis) and human papillomavirus (HPV, human papillomavirus) , hepatitis B virus (HBV, hepatitis B virus) and Hepatitis C virus (HCV, hepatitis C virus) infection.
Due to the potency of IFNβ against respiratory viruses and its effects on multiple cell types, IFNβ may have greater potential for development as a therapeutic agent than IFNα and IFNλ.
Strategies for intracellular nucleotide depletion to block viral replication
The idea that viral replication increases the cellular burden of available nucleotides could serve as a mechanism for interfering with viral replication.
Inosine 5′-monophosphate dehydrogenase ( IMPDH ) catalyzes an important step in the biosynthesis of guanine nucleotides (guanine nucleotides) , that is, converting IMP (inosine monophosphate) into xanthosine monophosphate (XMP, xanthosine monophosphate) .
XMP mediates the formation of guanosine monophosphate (GMP) , a key molecule in many cellular processes.
Inhibition of IMPDH leads to depletion of intracellular guanine nucleotide levels, limiting RNA and DNA synthesis required for viral replication .
Figure 3. IMPDH inhibitors block the process of guanosine monophosphate GMP synthesis
Examples of IMPDH inhibitors are VX-497 (Fig. 4) , a noncompetitive IMPDH inhibitor with broad-spectrum activity; [14] and ribavirin (Fig. 4) , which is a competitive IMPDH inhibitors (competitive or non-competitive refers to whether the inhibitor competes with the natural substrate for binding to the active site of the receptor.
If so, it is a competitive inhibitor; if the inhibitor binds to other site inhibits the substrate, it is a non-competitive inhibitor) .
Figure 4. Chemical structures of IMPDH inhibitors VX-497 and Ribavirin
Summary
Of the more than 90 approved antiviral drugs, HIV and HCV drugs account for two-thirds of all approved drugs. [15]
Antiviral drugs are dominated by small molecules, accounting for 87% of approved antiviral drugs.
Despite extensive research on host targets and their relevance in the antiviral life cycle, the number of approved antiviral drugs (HDAs) targeting host proteins lags significantly. Only about 10% of all approved antiviral drugs target host proteins, and half of these are interferon-related biologics. [16]
The clinical development and use of antiviral drugs requires careful consideration of their presumed benefits as well as their potential side effects.
The topic of drug-related adverse events (DAEs) and toxicity is almost unavoidable when targeting host proteins . Sources of DAEs include chemical-related toxicity or pathway-related toxicity.
The chemical toxicity of potential drugs is mainly caused by unstable functional groups.
Pathway-related toxicity, on the other hand, is related to the biological activity of the drug. One advantage of direct-acting antivirals ( DAAs) is that they attack viral proteins rather than host proteins, reducing theoretical concerns about off-target effects.
However, even with DAA, off-target effects are unavoidable because there are tens of thousands of known host proteins.
For host-directed antiviral HDAs, safety concerns are a central consideration, as targeting proteins or pathways important for cellular development and homeostasis should be avoided.
The cardiotoxicity exposed by HCQ (hydroxychloroquine, hydroxychloroquine) during the treatment of COVID-19 effectively illustrates this point. [17] In the development of HDAs, pathway-related toxicity requires more rigorous studies during the preclinical and translational stages of drug development.
Respiratory viral infections, such as those caused by influenza and coronaviruses, or hemorrhagic fevers caused by dengue or Zika viruses with pandemic potential, are acute infections that resolve within a few weeks.
Therefore, therapeutic strategies are characterized by short-term use, allowing a higher threshold for accepting non-fatal side effects. Notably, the FDA and the Data Safety Monitoring Board have pursued such risk management in the approval of anti-SARS-CoV-2 drugs.
The SARS-CoV-2 pandemic has highlighted the need for DAAs and HDAs in the antiviral drug arsenal, while also exposing shortcomings in our field of broad-spectrum antiviral drug development.
Taking history as a mirror, the research and development of broad-spectrum antiviral drugs should not be delayed again.
References:
[1] Ory, EM et al. The use and abuse of the broad spectrum antibiotics. JAMA. 1963, 185 (4): 273–279.
[2] Clayton L. Thomas, ed. (1993). Taber’s Cyclopedic Medical Dictionary (17th ed.). FA Davis Co.
[3] Hopkins, SJ (1997). Drugs and Pharmacology for Nurses (12th ed.). Churchill Livingstone.
[4] Ampicillin. The American Society of Health-System Pharmacists.
[5] Bekerman, E. et al. Infectious disease. Combating emerging viral threats. Science. 2015, 348 (6232): 282–283.
[6] drugvirus.info.
[7] García-Serradilla, M. et al. Drug repurposing for new, efficient, broad spectrum antivirals. Virus Research. 2019, 264: 22–31.
[8] Monk, P. The Need — And Opportunity — To Develop Broad-Spectrum Antivirals. Pharmaceutical Online. 03, 01, 2023.
[9] Vipul C. Chitalia, VC et al. A painful lesson from the COVID-19 pandemic: the need for broad-spectrum, host-directed antivirals. J Transl Med. 2020, 18, 390.
[10] Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–80.
[11] Kim, TS et al. Phenotypic analysis of mice lacking the Tmprss2-encoded protease. Mol Cell Biol. 2006;26:965–75.
[12] Laporte, M. et al. Airway proteases: an emerging drug target for influenza and other respiratory virus infections. Curr Opin Virol. 2017;24:16–24.
[13] Braun, E. et al. Furin-mediated protein processing in infectious diseases and cancer. Clin Transl Immunology. 2019;8:e1073.
[14] Markland, W. et al. Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob Agents Chemother. 2000; 44: 859–866.
[15] Chaudhuri, S. et al. Innovation and trends in the development and approval of antiviral medicines: 1987–2017 and beyond. Antiviral Res. 2018; 155: 76–88.
[16] De Clercq, E. et al. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev. 2016; 29: 695–747.
[17] Mercuro, NJ et al. Risk of QT interval progression associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2019.
Covid-19 brings thoughts on the development of broad-spectrum antiviral drugs
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