How biological catalysts both enable viral infection and provide pathways to treatment
When Sarah, a 42-year-old teacher, recovered from COVID-19, she thought the worst was behind her. But weeks later, she found herself struggling with dizzy spells and dramatic blood pressure swings that defied explanation. Like millions experiencing Long COVID, her body seemed to be fighting a battle that should have ended. What scientists discovered in people like Sarah might seem like science fiction: some COVID-19 patients develop catalytic antibodies—unusual immune warriors that behave like enzymes, potentially contributing to these mysterious symptoms 1 .
From the initial infection to the development of life-saving treatments, enzymes and enzyme-like molecules have been central characters in this pandemic story. This article explores how these biological workhorses have become both our adversaries and allies in the fight against SARS-CoV-2, and how researchers are turning them into powerful weapons for future battles.
Enzymes facilitate SARS-CoV-2 entry into human cells
Viral enzymes copy genetic material and process proteins
Antibodies with enzymatic activity may contribute to Long COVID
The story of SARS-CoV-2 infection begins with a precise molecular interaction. The virus's spike protein acts like a key seeking the right lock—and finds it in the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of our cells 5 .
Under normal circumstances, ACE2 plays a crucial role in regulating blood pressure by breaking down angiotensin II, a molecule that constricts blood vessels 1 . But when SARS-CoV-2 appears, it hijacks this helpful enzyme for its own purposes.
"The SARS-CoV-2 Spike protein receptor-binding domain (RBD) binds angiotensin converting enzyme 2 (ACE2) on the surface of host cells to initiate infection," researchers noted in a 2025 study 1 .
Binding alone isn't enough for SARS-CoV-2 to enter our cells—the spike protein needs activation through precise enzymatic cleavage:
During viral production, the spike protein is cleaved by human furin-like proteases into S1 and S2 subunits 5 .
Once the virus binds to ACE2, additional cuts are needed. Either TMPRSS2 (at the cell surface) or cathepsin L (inside cellular endosomes) cleaves the spike protein at a site called S2' 5 .
This final cleavage releases the fusion peptide, which initiates the merging of viral and cellular membranes 5 .
Once inside the cell, SARS-CoV-2 reveals its true nature as a molecular parasite, hijacking the cell's machinery to make countless copies of itself. Two viral enzymes play particularly crucial roles in this process.
Imagine the virus needs to build its components but can only produce them as one long, connected string of proteins. This is where the main protease (3CLpro) comes in—it acts as molecular scissors that cut the long polyprotein chain into functional viral pieces 9 .
"3CL-Pro plays a central role in progression of infection and generation of new viral particles," scientists explained in a 2021 study 9 .
While 3CLpro handles protein processing, the RNA-dependent RNA polymerase (RdRp) is responsible for copying the viral genetic material. This enzyme acts as a photocopier for RNA, creating countless copies of the viral genome to pack into new virus particles 2 .
Though the virus's proofreading mechanism (nsp14) reduces mutation rates compared to other RNA viruses, the RdRp still makes enough errors to allow for the concerning variants that have emerged throughout the pandemic .
In one of the most surprising twists of COVID-19 research, scientists discovered that some patients develop antibodies that behave like enzymes—so-called "abzymes" (catalytic antibodies). The theory behind their formation is fascinating: when the immune system creates antibodies against the spike protein's receptor-binding domain, some of these antibodies so closely mirror the structure of ACE2 that they develop similar catalytic activity 1 7 .
"We hypothesized that some people convalescing from COVID-19 may produce anti-RBD antibodies that resemble ACE2 sufficiently to have ACE2-like catalytic activity," researchers wrote in a groundbreaking 2025 study 1 .
To test whether these theoretical abzymes actually existed in recovering patients and whether they correlated with symptoms, researchers designed a careful clinical study.
| Characteristic | Finding | Significance |
|---|---|---|
| Percentage with abzymes | 6 of 20 patients (30%) | Demonstrates the phenomenon is not rare |
| Symptom association | Blood pressure instability | Suggests clinical relevance |
| Timing | Present in convalescent phase | Indicates persistence beyond acute infection |
| Abzyme type | Immunoglobulin-associated | Confirms immune system origin |
The findings were striking: six of the twenty research subjects (30%) had measurable ACE2-like antibody-associated catalytic activity in their plasma 1 . Even more importantly, the presence of this activity correlated with lower blood pressure after the 6-minute walk test 1 .
This discovery provides a potential biochemical explanation for some Long COVID symptoms. If these abzymes are active in the body, they might disrupt the delicate renin-angiotensin system that regulates blood pressure, potentially explaining the orthostatic intolerance and blood pressure instability reported by many Long COVID patients 1 7 .
Studying viral enzymes and developing treatments requires specialized tools. Here are some key reagents that have been essential in COVID-19 enzymology research:
| Reagent/Tool | Function | Research Application |
|---|---|---|
| Recombinant 3CLpro (Mpro) | Viral main protease | Screening for antiviral compounds 9 |
| ACE2 enzymatic assays | Measure ACE2 activity | Detecting abzyme activity in patient samples 1 |
| FRET-based protease substrates | Fluorescent detection of cleavage | High-throughput drug screening 9 |
| Vero CCL-81 cells | Mammalian cell line | Viral culture and inhibition studies 6 |
| SARS-CoV-2 anti-spike IgG assays | Measure immune response | Correlating antibody levels with enzymatic activity 1 |
The search for antiviral drugs has heavily focused on inhibiting key viral enzymes. Protease inhibitors target 3CLpro, while polymerase inhibitors aim to block RdRp 4 .
For instance, the drug molnupiravir works by targeting the viral replication machinery—it's a nucleoside analog that gets incorporated into the growing RNA chain, introducing mutations that ultimately fatal to the virus 3 .
Beyond targeting viral enzymes, scientists have engineered enzymes to improve antiviral drug production. Creating the molnupiravir supply needed for global distribution presented significant challenges until researchers developed an enzymatic cascade synthesis 3 .
They engineered a ribosyl kinase and uridine phosphorylase that could efficiently produce the drug precursor, increasing catalytic efficiency 80-100 fold through strategic mutations 3 .
| Therapeutic Approach | Target Enzyme | Mechanism of Action |
|---|---|---|
| Molnupiravir | RNA-dependent RNA polymerase | Introduces lethal mutations during viral replication 3 |
| Protease inhibitors (e.g., GC376) | 3CL main protease (3CLpro) | Blocks essential viral polyprotein cleavage 9 |
| Natural compounds (e.g., myricetin) | 3CL main protease | Covalently binds catalytic cysteine residue 9 |
| Abzyme research | ACE2-mimicking antibodies | Understanding and potentially mitigating Long COVID symptoms 1 |
The story of enzymatic catalysts in COVID-19 reveals a fundamental truth about virology: the very molecular machinery that enables viruses to thrive also presents opportunities to stop them. From the initial engagement between spike protein and ACE2 to the replication of viral genetic material and the unexpected appearance of antibody-enzymes in Long COVID, enzymes have been at the heart of both the disease's mechanism and our response to it.
What began as a desperate response to a global emergency has evolved into a sophisticated understanding of viral enzymology that will undoubtedly prepare us better for future outbreaks. The enzymatic catalysts that once seemed to favor the virus are increasingly being harnessed as powerful tools in our medical arsenal, proving that sometimes the smallest warriors make the biggest difference in the battles that shape our world.
Ongoing studies explore the role of enzymes in viral pathogenesis and treatment
Enzyme-targeting drugs offer promising avenues for COVID-19 treatment
Understanding viral enzymology prepares us for future pandemics