Potential Anti-SARS-CoV-2 Therapeutics That Target the Post-Entry Stages of the Viral Life Cycle: A Comprehensive Review

Abstract

The coronavirus disease-2019 (COVID-19) pandemic continues to challenge health care systems around the world. Scientists and pharmaceutical companies have promptly responded by advancing potential therapeutics into clinical trials at an exponential rate. Initial encouraging results have been realized using remdesivir and dexamethasone. Yet, the research continues so as to identify better clinically relevant therapeutics that act either as prophylactics to prevent the infection or as treatments to limit the severity of COVID-19 and substantially decrease the mortality rate. Previously, we reviewed the potential therapeutics in clinical trials that block the early stage of the viral life cycle. In this review, we summarize potential anti-COVID-19 therapeutics that block/inhibit the post-entry stages of the viral life cycle. The review presents not only the chemical structures and mechanisms of the potential therapeutics under clinical investigation, i.e., listed in clinicaltrials.gov, but it also describes the relevant results of clinical trials. Their anti-inflammatory/immune-modulatory effects are also described. The reviewed therapeutics include small molecules, polypeptides, and monoclonal antibodies. At the molecular level, the therapeutics target viral proteins or processes that facilitate the post-entry stages of the viral infection. Frequent targets are the viral RNA-dependent RNA polymerase (RdRp) and the viral proteases such as papain-like protease (PLpro) and main protease (Mpro). Overall, we aim at presenting up-to-date details of anti-COVID-19 therapeutics so as to catalyze their potential effective use in fighting the pandemic.

In Vitro Assessment of the Antiviral Activity of Ketotifen, Indomethacin and Naproxen, Alone and in Combination, against SARS-CoV-2

“…In relation to the aim of the combination products to reduce excessive immune response, both indomethacin and naproxen have shown to reduce interleukin (IL)-6 in the plasma and synovial fluids of rheumatoid arthritis patients [ 36 ], and in another study indomethacin reduced inflammation in Alzheimer patients [ 37 ]. These findings suggest that both naproxen and indomethacin may be effective in counteracting the cytokine storm associated with SARS CoV-2 infection [ 38 , 39 , 40 ].…”

Plitidepsin, an inhibitor of the cell elongation factor eEF1a, and molnupiravir an analogue of the ribonucleoside cytidine, two new chemical compounds with intense activity against SARS-CoV-2

“…sable de que la mayoría de los coronavirus, incluido el SARS-CoV-2, se muestren resistentes a muchos análogos, incluyendo la ribavirina y el 5-fluoruracilo [16,17]. Por lo tanto, los nuevos análogos han de ser capaces de inhibir a los coronavirus en presencia de la actividad de la nsp14-ExoN [14][15][16][17].…”

“…Este profármaco posee una elevada biodisponibilidad oral y es fosforilado en el grupo N4hidroxilo a nivel del tracto gastrointestinal. Posteriormente es hidrolizado para dar lugar al fármaco original (EIDD-1931) que se distribuye a los diferentes tejidos para ser tri-fosforilado por las células eucariotas (forma activa) [15,17,18]. El compuesto tri-fosforilado presenta un amplio espectro antiviral frente a los virus ARN, tales como la gripe, Ebola, virus de la encefalitis equina venezolana y Coronavirus (MERS, SARS-1 y SARS-CoV-2) [17,18].…”

“…Posteriormente es hidrolizado para dar lugar al fármaco original (EIDD-1931) que se distribuye a los diferentes tejidos para ser tri-fosforilado por las células eucariotas (forma activa) [15,17,18]. El compuesto tri-fosforilado presenta un amplio espectro antiviral frente a los virus ARN, tales como la gripe, Ebola, virus de la encefalitis equina venezolana y Coronavirus (MERS, SARS-1 y SARS-CoV-2) [17,18]. Se ha mostrado eficaz incluso frente a las cepas del SARS-CoV-2 resistentes a remdesivir [17,19].…”

Therapeutic approaches for SARS-CoV-2 infection

“…Parallelly, the collective scientific community has been trying to explore and target the key proteins of SARS-CoV-2 mutant’s pathogenesis including after infection human immuno-pathophysiology. Subsequently, a lot of data has been reported in terms of review articles that describe hosts responses, clinical features, proposed treatment interventions and their mechanism of action (MOA) associated with SARS-CoV-2 infection or COVID-19 [1] , [2] , [3] , [4] , [5] , [6] , [7] . Nevertheless, research on SARS-CoV-2 and COVID-19 is progressing with time in terms of rational design of novel drugs, natural products drug discovery, immuno-pathological and clinical outcomes based on host nutritional, metabolic and lifestyle status, role of herbo-mineral formulations in innate/adaptive immunity modulation to contain the disease.…”