ABSTRACT
The emergence and rapid spread of novel coronavirus disease (COVID-19) has posed a serious challenge to global public health in 2020. The speed of this viral spread together with the high mortality rate has caused an unprecedented public health crisis. With no antivirals or vaccines available for the treatment of COVID-19, the medical community is presently exploring repositioning of clinically approved drugs for COVID-19. Chloroquine (CQ) and hydroxychloroquine (HCQ) have emerged as potential candidates for repositioning as anti-COVID-19 therapeutics and have received FDA authorization for compassionate use in COVID-19 patients. On March 28, 2020, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for HCQ in the treatment of COVID-19. However, it was later revoked by the FDA on June 15, 2020, after analyzing the emerging scientific data from ongoing clinical trials. Similarly, the World Health Organization (WHO) also conducted a Solidarity trial of chloroquine, hydroxychloroquine, remdesivir, lopinavir, and ritonavir. However, on May 23, 2020, the executive body of the "Solidarity trial" decided to put a temporary hold on the HCQ trial. On June 17, 2020, the WHO abruptly stopped the Solidarity trial of HCQ. The current review strives to examine the basis of compassionate use of CQ and HCQ for the treatment of COVID-19 in terms of literature evidence, establishing the antiviral efficacy of these drugs against corona and related viruses. Furthermore, the review presents a critical analysis of the clinical trial findings and also provides an insight into the dynamically changing decision on the authorization and withdrawal of HCQ as anti-COVID-19 therapy by the U.S. FDA and the WHO. Ultimately, our study necessitates an evidenced-based treatment protocol to confront the ongoing COVID-19 pandemic and not the mere observational study that mislead the public healthcare system, which paralyzes the entire world.
ABSTRACT
COVID-19 pandemic has spread worldwide at an exponential rate affecting millions of people instantaneously. Currently, various drugs are under investigation to treat an enormously increasing number of COVID-19 patients. This dreadful situation clearly demands an efficient strategy to quickly identify drugs for the successful treatment of COVID-19. Hence, drug repurposing is an effective approach for the rapid discovery of frontline arsenals to fight against COVID-19. Successful application of this approach has resulted in the repurposing of some clinically approved drugs as potential anti-SARS-CoV-2 candidates. Several of these drugs are either antimalarials, antivirals, antibiotics or corticosteroids and they have been repurposed based on their potential to negate virus or reduce lung inflammation. Large numbers of clinical trials have been registered to evaluate the effectiveness and clinical safety of these drugs. Till date, a few clinical studies are complete and the results are primary. WHO also conducted an international, multi-country, open-label, randomized trials-a solidarity trial for four antiviral drugs. However, solidarity trials have few limitations like no placebos were used, additionally any drug may show effectiveness for a particular population in a region which may get neglected in solidarity trial analysis. The ongoing randomized clinical trials can provide reliable long-term follow-up results that will establish both clinical safety and clinical efficacy of these drugs with respect to different regions, populations and may aid up to worldwide COVID-19 treatment research. This review presents a comprehensive update on majorly repurposed drugs namely chloroquine, hydroxychloroquine, remdesivir, lopinavir-ritonavir, favipiravir, ribavirin, azithromycin, umifenovir, oseltamivir as well as convalescent plasma therapy used against SARS-CoV-2. The review also summarizes the data recorded on the mechanism of anti-SARS-CoV-2 activity of these repurposed drugs along with the preclinical and clinical findings, therapeutic regimens, pharmacokinetics, and drug-drug interactions.
ABSTRACT
SARS-CoV-2 transmissibility is higher than that of other human coronaviruses; therefore, it poses a threat to the populated communities. We investigated mutations among envelope (E), membrane (M), and spike (S) proteins from different isolates of SARS-CoV-2 and plausible signaling influenced by mutated virus in a host. We procured updated protein sequences from the NCBI virus database. Mutations were analyzed in the retrieved sequences of the viral proteins through multiple sequence alignment. Additionally, the data was subjected to ScanPROSITE to analyse if the mutations generated a relevant sequence for host signaling. Unique mutations in E, M, and S proteins resulted in modification sites like PKC phosphorylation and N-myristoylation sites. Based on structural analysis, our study revealed that the D614G mutation in the S protein diminished the interaction with T859 and K854 of adjacent chains. Moreover, the S protein of SARS-CoV-2 consists of an Arg-Gly-Asp (RGD) tripeptide sequence, which could potentially interact with various members of integrin family receptors. RGD sequence in S protein might aid in the initial virus attachment. We speculated crucial host pathways which the mutated isolates of SARS-CoV-2 may alter like PKC, Src, and integrin mediated signaling pathways. PKC signaling is known to influence the caveosome/raft pathway which is critical for virus entry. Additionally, the myristoylated proteins might activate NF-κB, a master molecule of inflammation. Thus the mutations may contribute to the disease pathogenesis and distinct lung pathophysiological changes. Further the frequently occurring mutations in the protein can be studied for possible therapeutic interventions.