SUMMARY:
Researchers from UCLA’s Department of Medicine have developed an oral antiviral using the apoA-I mimetic peptide 4F alone or in combination with statins to prevent and treat infection of SARS-CoV-2, including long-term post-infection symptoms. ApoA-I mimetic peptides can also be given systemically as injection to attenuate viral replication associated inflammation and tissue injury that drive severe COVID-19.
BACKGROUND:
SARS-CoV-2 (COVID-19) is a highly transmissible disease responsible for the global pandemic that has caused more than 380 million infections and more than 5.7 million deaths. While vaccines have been a pivotal tool in easing the pandemic and preventing severe illness and hospitalization from COVID-19, the Omicron variant has highlighted their limited efficacy against preventing infection altogether and blocking transmission of emergent strains as the virus continues to mutate. Oral antivirals are an important countermeasure against emerging SARS-CoV-2 variants, complementary to vaccines and monoclonal antibodies, that will help our defense against COVID-19 be more enduring because they are cheaper to manufacture and easier to administer in non-hospital settings. However, current antivirals, such as remdesevir or Pfizer’s Paxlovid, have major limitations, including lack of anti-inflammatory effects, off-target effects in multiple organ systems resulting in serious side effects, and cannot be used long term as preexposure prophylaxis against COVID-19 or for long COVID. Thus, there is an unmet need to develop an efficacious, orally available, and safe therapeutic strategy to combat and even prevent COVID-19 infection.
INNOVATION:
UCLA researchers in the Department of Medicine have developed a novel antiviral strategy with the combined use of oral statins and the apoA-I mimetic 4F peptide that can additively target several host mechanisms that favor the replication of SARS-CoV-2. They found that in SARS-CoV-2 infected human lung epithelial Calu3 cells, 4F downregulates mitochondrial reactive oxygen species and CD147, a host protein that mediates viral entry. 4F further attenuates entry of SARS-CoV-2 viral entry by binding to and reducing bioactive proinflammatory lipids with higher affinity than apoA-1. The UCLA researchers also demonstrated that 4F upregulates inducers of the interferon pathway, a key pathway for host antiviral responses against, not only COVID-19, but also several DNA viruses such as HPV, adenovirus, and herpesviruses. Additionally, they found that 4F reduces associated cellular apoptosis and secretion of the proinflammatory biomarkers IL-6 and IL-1ß in both SARS-CoV-2 infected Calu3 cells and Vero E6 cells, a cell line highly susceptible to SARS-CoV-2 infection. Taken together, 4F attenuates in vitro SARS-CoV-2 replication and, unlike current antiviral drugs, diminishes lung tissue damage. Since animal and human studies have shown that statins may have major additive in vivo effects on altered lipid levels, systemic oxidative stress, and inflammation when administered in combination with 4F, the combined use of oral statins and 4F could have a profound impact on the course of the pandemic.
POTENTIAL APPLICATIONS:
● Effective antiviral treatment strategy for present and future strains and variants of SARS-CoV-2 that could reduce the risk of hospitalization and death
● Attenuate proviral and proinflammatory effects of bioactive lipids in a host of other viral infections, including but not limited to coronaviruses, gastrointestinal viruses, flaviviruses, HIV, hepatitis viruses, and rhabdoviridae
● Long-term preexposure prophylaxis against viral infections in high-risk groups that have comorbidities and are either immunocompromised or have contraindications for a vaccine
● Long -term treatment of long term sequalae of SARS-CoV-2 infection and other viral infections given the anti-inflammatory and antiapoptotic effects of apoA-I mimetic peptides
ADVANTAGES:
● Has antiviral, antiapoptotic, antioxidant, and anti-inflammatory effects on SARS-CoV-2 infected cells, suggesting that it may have multiple favorable therapeutic effects on COVID-19 infection
● Can attenuate potentially long-term cardiovascular effects of SARS-CoV-2 infection and Long COVID
● Oral administration allows for more rapid treatment to a larger population of patients
● Systemic administration through injection may also be used for acute severe viral infections
● 4F peptide has been previously tested in clinical trials and shown to be safe in murine models and humans when given orally or parenterally
DEVELOPMENT-TO-DATE:
Researchers have demonstrated the impact of 4F in attenuating symptoms of SARS-CoV-2 in vitro in mammalian cell lines.
Related Papers (from the inventors only):
Kelesidis, T.; Sharma, M.; Petcherski, A.; Hugo, C.; O’Connor, E.; Hultgren, N.W.; Ritou, E.; Williams, D.S.; Shirihai, O.S.; Reddy, S.T. Virulence 2021, 12.