by Dual role of nirmatrelvir and bisphosphonates in COVID-19 treatment and immunity
As the COVID-19 pandemic continues to affect people worldwide, the development of effective vaccines has been crucial in controlling the spread of the virus. However, there is still a need for antiviral treatments, especially for individuals who are unable to receive vaccines or are hesitant to do so. In a recent review published in the journal Cellular & Molecular Immunology, researchers delve into the therapeutic benefits of nirmatrelvir and its potential impact on the immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Additionally, the review discusses the immunomodulatory properties of bisphosphonates, a class of drugs traditionally used to treat bone disorders, and their potential role in combating severe SARS-CoV-2 infection.
Nirmatrelvir is an orally administered drug that targets the main proteinase (Mpro) of SARS-CoV-2. Specifically, it focuses on the 3-chymotrypsin-like cysteine protease (3CLPro), which cleaves two polyproteins encoded by the SARS-CoV-2 ribonucleic acid (RNA) genome, namely pp1a and pp1ab. By targeting this protease, nirmatrelvir is able to exert antiviral effects.
Paxlovid is a combination treatment of nirmatrelvir and ritonavir that has shown promising results in reducing hospitalization and death due to COVID-19 by up to 86%. Despite its efficacy in treating COVID-19, the impact of nirmatrelvir on the adaptive immune response to SARS-CoV-2 remains unclear.
In murine models, nirmatrelvir treatment reduced the levels of SARS-CoV-2-specific antibodies and T-cells, thus preventing severe infection. Additionally, secondary viral exposure further decreased the recruitment of memory B- and T-cells. These findings suggest that while nirmatrelvir effectively prevents severe disease by reducing viral titers, it may also affect the ability of the immune system to recognize and combat SARS-CoV-2 in the future. Several mechanisms have been proposed to explain this effect, including the limitation of SARS-CoV-2 antigen exposure to the immune system, which compromises the response of naive T- and B-cells.
Before the development and widespread implementation of COVID-19 vaccines, scientists explored the potential of repurposing existing drugs for the treatment of the viral disease. Many drugs were evaluated through in silico and in vitro analyses to determine their suitability for COVID-19 treatment.
Beyond their established role in inhibiting bone resorption by osteoclasts, bisphosphonates have been found to have various immunomodulatory effects. These drugs are commonly used to treat conditions such as osteoporosis, Paget’s disease, malignancy-induced hypercalcemia, and as an adjuvant in certain breast cancer treatments.
Bisphosphonates can be categorized into amino-bisphosphonates and non-amino-bisphosphonates based on their chemical composition. Amino-bisphosphonates have been shown to modulate different types of immune cells, including neutrophils, monocytes, γδT cells, and macrophages. Animal studies have demonstrated that both amino and non-amino bisphosphonates can enhance antibody and T-cell responses to viral antigens.
To assess the potential clinical utility of bisphosphonates in COVID-19 treatment, a retrospective study investigated whether prior bisphosphonate treatment influenced COVID-19 outcomes. Interestingly, individuals who had been treated with amino-bisphosphonates had a three- to five-fold reduced risk of being diagnosed with COVID-19 or of being hospitalized for the condition.
Further studies are needed to fully evaluate the potential use of bisphosphonates as prophylactic agents for individuals at a higher risk of severe COVID-19. It is crucial to comprehensively assess the long-term implications of all COVID-19 prevention and treatment interventions on antiviral immunity in order to understand the full range of effects these agents might have on the host immune response.
While numerous COVID-19 therapeutics have shown promising results in randomized controlled trials, more comprehensive data is necessary to establish definitive conclusions regarding their long-term impact. Balancing immediate treatment with long-term immunity is essential in managing the spread of SARS-CoV-2 and preventing severe COVID-19 outcomes. As such, it is imperative to combine all therapeutic solutions for COVID-19 with rigorous scientific research.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
