Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China.

The ongoing COVID-19 pandemic has resulted in millions of deaths globally, highlighting the need to develop potent prophylactic and therapeutic strategies against SARS-CoV-2. Small molecule inhibitors (remdesivir, Paxlovid, and molnupiravir) are essential complements to vaccines and play important roles in clinical treatment of SARS-CoV-2. Many advances have been made in development of anti-SARS-CoV-2 inhibitors in China, but progress in discovery and characterization of pharmacological activity, antiviral mechanisms, and clinical efficacy are limited. We review development of small molecule anti-SARS-CoV-2 drugs (azvudine [approved by the NMPA of China on July 25, 2022], VV116 [approved by the NMPA of China on January 29, 2023], FB2001, WPV01, pentarlandir, and cepharanthine) in China and summarize their pharmacological activity, potential mechanisms of action, clinical trials and use, and important milestones in their discovery. The role of structural biology in drug development is also reviewed. Future studies should focus on development of diverse second-generation inhibitors with excellent oral bioavailability, superior plasma half-life, increased antiviral activity against SARS-CoV-2 and its variants, high target specificity, minimal side effects, reduced drug-drug interactions, and improved lung histopathology.

Unraveling the mechanism of action of cepharanthine for the treatment of novel coronavirus pneumonia (COVID-19) from the perspectives of systematic pharmacology

Graphical abstract Natural products play an irreplaceable role in the treatment of SARS-CoV-2 infection. Nevertheless, the underlying molecular mechanisms involved remain elusive. To better understand their potential therapeutic effects, more validation studies are needed to explore underlying mechanisms systematically. This study aims to explore the potential targets of action and signaling pathways of cepharanthine for the treatment of COVID-19. This study revealed that a total of 173 potential targets of action for Cepharanthine and 86 intersectional targets for Cepharanthine against COVID-19 were screened and collected. Gene Ontology enrichment analysis suggested that inflammatory, immune cell and enzyme activities were the critical terms for cepharanthine against COVID-19. Pathway enrichment analysis showed that five pathways associated with COVID-19 were the main signaling pathways for the treatment of COVID-19 via cepharanthine. Molecular docking and molecular dynamics simulations suggested that 6 core targets were regarded as potential targets for cepharanthine against COVID-19. In brief, the study demonstrates that cepharanthine may play an important role in the treatment of SARS-CoV-2 infection through its harmonious activity against SARS-CoV-2 pathways and multiple related targets. This article provides valuable insights required to respond effectively to concerns of western medical community.

Unraveling the mechanism of action of cepharanthine for the treatment of novel coronavirus pneumonia (COVID-19) from the perspectives of systematic pharmacology.

Natural products play an irreplaceable role in the treatment of SARS-CoV-2 infection. Nevertheless, the underlying molecular mechanisms involved remain elusive. To better understand their potential therapeutic effects, more validation studies are needed to explore underlying mechanisms systematically. This study aims to explore the potential targets of action and signaling pathways of cepharanthine for the treatment of COVID-19. This study revealed that a total of 173 potential targets of action for Cepharanthine and 86 intersectional targets for Cepharanthine against COVID-19 were screened and collected. Gene Ontology enrichment analysis suggested that inflammatory, immune cell and enzyme activities were the critical terms for cepharanthine against COVID-19. Pathway enrichment analysis showed that five pathways associated with COVID-19 were the main signaling pathways for the treatment of COVID-19 via cepharanthine. Molecular docking and molecular dynamics simulations suggested that 6 core targets were regarded as potential targets for cepharanthine against COVID-19. In brief, the study demonstrates that cepharanthine may play an important role in the treatment of SARS-CoV-2 infection through its harmonious activity against SARS-CoV-2 pathways and multiple related targets. This article provides valuable insights required to respond effectively to concerns of western medical community.

Oral GS-441524 derivatives: Next-generation inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase.

GS-441524, an RNA-dependent RNA polymerase (RdRp) inhibitor, is a 1'-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS-441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524.

Bioactive natural products in COVID-19 therapy.

The devastating COVID-19 pandemic has caused more than six million deaths worldwide during the last 2 years. Effective therapeutic agents are greatly needed, yet promising magic bullets still do not exist. Numerous natural products (cordycepin, gallinamide A, plitidepsin, telocinobufagin, and tylophorine) have been widely studied and play a potential function in treating COVID-19. In this paper, we reviewed published studies (from May 2021 to April 2022) relating closely to bioactive natural products (isolated from medicinal plants, animals products, and marine organisms) in COVID-19 therapy in vitro to provide some essential guidance for anti-SARS-CoV-2 drug research and development.

Broad-spectrum prodrugs with anti-SARS-CoV-2 activities: Strategies, benefits, and challenges.

In this era, broad-spectrum prodrugs with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activities are gaining considerable attention owing to their potential clinical benefits and role in combating the fast-spreading coronavirus disease 2019 (COVID-19) pandemic. The last 2 years have seen a surge of reports on various broad-spectrum prodrugs against SARS-CoV-2, and in in vitro studies, animal models, and clinical practice. Currently, only remdesivir (with many controversies and limitations) has been approved by the U.S. FDA for the treatment of SARS-CoV-2 infection, and additional potent anti-SARS-CoV-2 drugs are urgently required to enrich the defense arsenals. The world has ubiquitously grappled with the COVID-19 pandemic, and the availability of broad-spectrum prodrugs provides great hope for us to subdue this global threat. This article reviews promising treatment strategies, antiviral mechanisms, potential benefits, and daunting clinical challenges of anti-SARS-CoV-2 agents to provide some important guidance for future clinical treatment.

Co-crystallization and structure determination: An effective direction for anti-SARS-CoV-2 drug discovery.

Safer and more-effective drugs are urgently needed to counter infections with the highly pathogenic SARS-CoV-2, cause of the COVID-19 pandemic. Identification of efficient inhibitors to treat and prevent SARS-CoV-2 infection is a predominant focus. Encouragingly, using X-ray crystal structures of therapeutically relevant drug targets (PLpro, Mpro, RdRp, and S glycoprotein) offers a valuable direction for anti-SARS-CoV-2 drug discovery and lead optimization through direct visualization of interactions. Computational analyses based primarily on MMPBSA calculations have also been proposed for assessing the binding stability of biomolecular structures involving the ligand and receptor. In this study, we focused on state-of-the-art X-ray co-crystal structures of the abovementioned targets complexed with newly identified small-molecule inhibitors (natural products, FDA-approved drugs, candidate drugs, and their analogues) with the assistance of computational analyses to support the precision design and screening of anti-SARS-CoV-2 drugs.

Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer.

As a public health emergency of international concern, the highly contagious coronavirus disease 2019 (COVID-19) pandemic has been identified as a severe threat to the lives of billions of individuals. Lung cancer, a malignant tumor with the highest mortality rate, has brought significant challenges to both human health and economic development. Natural products may play a pivotal role in treating lung diseases. We reviewed published studies relating to natural products, used alone or in combination with US Food and Drug Administration-approved drugs, active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lung cancer from 1 January 2020 to 31 May 2021. A wide range of natural products can be considered promising anti-COVID-19 or anti-lung cancer agents have gained widespread attention, including natural products as monotherapy for the treatment of SARS-CoV-2 (ginkgolic acid, shiraiachrome A, resveratrol, and baicalein) or lung cancer (daurisoline, graveospene A, deguelin, and erianin) or in combination with FDA-approved anti-SARS-CoV-2 agents (cepharanthine plus nelfinavir, linoleic acid plus remdesivir) and anti-lung cancer agents (curcumin and cisplatin, celastrol and gefitinib). Natural products have demonstrated potential value and with the assistance of nanotechnology, combination drug therapies, and the codrug strategy, this "natural remedy" could serve as a starting point for further drug development in treating these lung diseases.

Chinese herbal medicine: Fighting SARS-CoV-2 infection on all fronts.

ETHNOPHARMACOLOGICAL RELEVANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19), a highly pathogenic virus that has spread rapidly across the entire world. There is a critical need to develop safe and effective drugs, especially broad-spectrum antiviral and organ protection agents in order to treat and prevent this dangerous disease. It is possible that Chinese herbal medicine may play an essential role in the treatment of patients with SARS-CoV-2 infection. AIM OF THE REVIEW: We aim to review the use of Chinese herbal medicine in the treatment of COVID-19 both in vitro and in clinical practice. Our goal was to provide a better understanding of the potential therapeutic effects of Chinese herbal medicine and to establish a "Chinese protocol" for the treatment of COVID-19. MATERIALS AND METHODS: We systematically reviewed published research relating to traditional Chinese herbal medicines and the treatment of SARS-CoV-2 from inception to the 6th January 2021 by screening a range of digital databases (Web of Science, bioRxiv, medRxiv, China National Knowledge Infrastructure, X-MOL, Wanfang Data, Google Scholar, PubMed, Elsevier, and other resources) and public platforms relating to the management of clinical trials. We included the active ingredients of Chinese herbal medicines, monomer preparations, crude extracts, and formulas for the treatment of COVID-19. RESULTS: In mainland China, a range of Chinese herbal medicines have been recognized as very promising anti-SARS-CoV-2 agents, including active ingredients (quercetagetin, osajin, tetrandrine, proscillaridin A, and dihydromyricetin), monomer preparations (xiyanping injection, matrine-sodium chloride injection, diammonium glycyrrhizinate enteric-coated capsules, and sodium aescinate injection), crude extracts (Scutellariae Radix extract and garlic essential oil), and formulas (Qingfei Paidu decoction, Lianhuaqingwen capsules, and Pudilan Xiaoyan oral liquid). All these agents have potential activity against SARS-CoV-2 and have attracted significant attention due to their activities both in vitro and in clinical practice. CONCLUSIONS: As a key component of the COVID-19 treatment regimen, Chinese herbal medicines have played an irreplaceable role in the treatment of SARS-CoV-2 infection. The "Chinese protocol" has already demonstrated clear clinical importance. The use of Chinese herbal medicines that are capable of inhibiting SARS-Cov-2 infection may help to address this immediate unmet clinical need and may be attractive to other countries that are also seeking new options for effective COVID-19 treatment. Our analyses suggest that countries outside of China should also consider protocols involving Chinese herbal medicines combat this fast-spreading viral infection.

Turning the Tide: Natural Products and Natural-Product-Inspired Chemicals as Potential Counters to SARS-CoV-2 Infection.

The novel and highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has become a continued focus of global attention due to the serious threat it poses to public health. There are no specific drugs available to combat SARS-CoV-2 infection. Natural products (carolacton, homoharringtonine, emetine, and cepharanthine) and natural product-inspired small molecules (ivermectin, GS-5734, EIDD-2801, and ebselen) are potential anti-SARS-CoV-2 agents that have attracted significant attention due to their broad-spectrum antiviral activities. Here, we review the research on potential landmark anti-SARS-CoV-2 agents, systematically discussing the importance of natural products and natural-product-inspired small molecules in the research and development of safe and effective antiviral agents.

GS-5734: a potentially approved drug by FDA against SARS-Cov-2

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. COVID-19 is an ongoing global health crisis. Efficacious drugs against COVID-19 are not yet available. Therefore, rapid discovery of safe and efficacious agents against SARS-CoV-2 are needed urgently. Nucleoside analogs have an integral role in the treatment of viral infections. Owing to their broad-spectrum antiviral activities, C-nucleoside analogs have become key components of COVID-19 treatment regimens. Here, we review the state-of-the-art C-nucleoside GS-5734 (remdesivir) that is in preclinical research for COVID-19 treatment. As a potentially approved drug by the FDA against SARS-Cov-2 infection, the efficacy and safety of GS-5734 have been documented repeatedlyin vitro, in animal models, and in humans. To better understand the drug-development process, this review focused on the discovery process, preparation methods, broad-spectrum activities, and antiviral mechanism of GS-5734.