Abstract The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has caused devastating impacts on the public health and the global economy. Rapid viral antigenic evolution has led to the continual generation of new variants. Of special note is the recently expanding Omicron subvariants that are capable of immune evasion from most of the existing neutralizing antibodies (nAbs). This has posed new challenges for the prevention and treatment of COVID-19. Therefore, exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In sharp contrast to the massive accumulation of mutations within the SARS-CoV-2 receptor-binding domain (RBD), the S2 fusion subunit has remained highly conserved among variants. Hence, S2-based therapeutics may provide effective cross-protection against new SARS-CoV-2 variants. Here, we summarize the most recently developed broad-spectrum fusion inhibitors (e.g., nAbs, peptides, proteins, and small-molecule compounds) and candidate vaccines targeting the conserved elements in SARS-CoV-2 S2 subunit. The main focus includes all the targetable S2 elements, namely, the fusion peptide, stem helix, and heptad repeats 1 and 2 (HR1-HR2) bundle. Moreover, we provide a detailed summary of the characteristics and action-mechanisms for each class of cross-reactive fusion inhibitors, which should guide and promote future design of S2-based inhibitors and vaccines against new coronaviruses. 

/pdf/targetable-elements-in-sars-cov-2-s2-subunit-for-the-design-1tffpnc6.pdf

Targetable elements in SARS-CoV-2 S2 subunit for the design of pan-coronavirus fusion inhibitors and vaccines

Recent developments in animal venom peptide nanotherapeutics with improved selectivity for cancer cells

The COVID-19 pandemic, caused by SARS-CoV-2, has had a huge impact on global health. To respond to rapidly mutating viruses and to prepare for the next pandemic, there is an urgent need to develop small molecule therapies that target critical stages of the SARS-CoV-2 life cycle. Inhibiting the entry process of the virus can effectively control viral infection and play a role in prevention and treatment. Host factors involved in this process, such as ACE2, TMPRSS2, ADAM17, furin, PIKfyve, TPC2, CTSL, AAK1, V-ATPase, HSPG, and NRP1, have been found to be potentially good targets with stability. Through further exploration of the cell entry process of SARS-CoV-2, small-molecule drugs targeting these host factors have been developed. This review focuses on the structural functions of potential host cell targets during the entry of SARS-CoV-2 into host cells. The research progress, chemical structure, structure-activity relationship, and clinical value of small-molecule inhibitors against COVID-19 are reviewed to provide a reference for the development of small-molecule drugs against COVID-19. 

Targeting SARS-CoV-2 entry processes: The promising potential and future of host-targeted small-molecule inhibitors.

Since the SARS-CoV-2 outbreak, pharmaceutical companies and researchers worldwide have worked hard to develop vaccines and drugs to end the SARS-CoV-2 pandemic. The potential pathogen responsible for Coronavirus Disease 2019 (COVID-19), SARS-CoV-2, belongs to a novel lineage of beta coronaviruses in the subgenus arbovirus. Antiviral drugs, convalescent plasma, monoclonal antibodies, and vaccines are effective treatments for SARS-CoV-2 and are beneficial in preventing infection. Numerous studies have already been conducted using the genome sequence of SARS-CoV-2 in comparison with that of other SARS-like viruses, and numerous treatments/prevention measures are currently undergoing or have already undergone clinical trials. We summarize these studies in depth in the hopes of highlighting some key details that will help us to better understand the viral origin, epidemiology, and treatments of the virus.

/pdf/sars-cov-2-an-updated-review-highlighting-its-evolution-and-uoqrlcol.pdf

SARS-CoV-2: An Updated Review Highlighting Its Evolution and Treatments

Cancer is the most common cause of human death worldwide, posing a serious threat to human health and having a negative impact on the economy. In the past few decades, significant progress has been made in anticancer therapies, but traditional anticancer therapies, including radiation therapy, surgery, chemotherapy, molecular targeted therapy, immunotherapy and antibody-drug conjugates (ADCs), have serious side effects, low specificity, and the emergence of drug resistance. Therefore, there is an urgent need to develop new treatment methods to improve efficacy and reduce side effects. Antimicrobial peptides (AMPs) exist in the innate immune system of various organisms. As the most promising alternatives to traditional drugs for treating cancers, some AMPs also have been proven to possess anticancer activities, which are defined as anticancer peptides (ACPs). These peptides have the advantages of being able to specifically target cancer cells and have less toxicity to normal tissues. More and more studies have found that marine and terrestrial animals contain a large amount of ACPs. In this article, we introduced the animal derived AMPs with anti-cancer activity, and summarized the types of tumor cells inhibited by ACPs, the mechanisms by which they exert anti-tumor effects and clinical applications of ACPs.

Anticancer activities of natural antimicrobial peptides from animals

Aims: To evaluate anti-tumour effects and mechanism of novel BF-30 derivative via cell-based assays and melanoma-bearing model mice. Main methods: BF-30 derivatives were designed by fusing heptapeptide-palmitic tags to native BF-30 via a protease-cleavable linker and prepared by F-moc solid-phase synthesis. Albumin binding affinity test and in vitro control-released assay were performed to screen these BF-30 derivatives and explore the mechanism of anti-tumour effects. The selected BF-30 derivative was further subjected to the preclinical efficacy study and chronic evaluation of anti-tumour effects melanoma-bearing model mice. Key findings: Twenty-one BF-30 derivatives, termed LBF-1 to LBF-21, were obtained with high purity and accurate molecular weight. Surface plasmon resonance (SPR) measurements, plasma stability test and in vitro control-released assay all showed that LBF-14 exerted better druggability compared with the others. Moreover, LBF-14 was proved to inhibit the proliferation of B16F10 melanoma cell by disrupting the cytoplasmic membrane and binding to genomic DNA to prevent transcription. Furthermore, half-life of intact LBF-14 and released BF-30 in rhesus monkeys were approximately 120.9 h and 136.4 h, respectively, after a single subcutaneous injection of 0.9 mg/kg LBF-14. In addition, chronic treatment of LBF-14 significantly suppressed melanoma growth and improved the survival rate of B16F10-bearing mice with the observed inhibition of 63.5% for 0.3mg/kg and 91.5% for 0.9 mg/kg. Furthermore, results of H&E staining prove that chronic treatment of LBF-30 effectively suppressed metastasis and invasion of B16F10 cells. Significance: LBF-14 holds potential to be developed as a promising once-weekly candidate for the treatment of malignant melanoma.

/pdf/design-and-biological-evaluation-of-novel-bf-30-analogs-for-1wfvf0cz57.pdf

Design and biological evaluation of novel BF-30 analogs for the treatment of malignant melanoma

Abstract Background: To date, there is no effective medicine to treat coronavirus disease 2019 (COVID-19), and the antiviral efficacy of arbidol in the treatment for COVID-19 remained equivocal and controversial. The purpose of this study was to evaluate the efficacy and safety of arbidol tablets in the treatment of COVID-19. Methods: This was a prospective, open-label, controlled and multicenter investigator-initiated trial involving adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were stratified 1:2 to either standard-of-care (SOC) or SOC plus arbidol tablets (oral administration of 200 mg per time, three times a day for 14 days). The primary endpoint was negative conversion of SARS-CoV-2 within the first week. The rates and 95% confidential intervals were calculated for each variable. Results: A total of 99 patients with laboratory-confirmed SARS-CoV-2 infection were enrolled; 66 were assigned to the SOC plus arbidol tablets group, and 33 to the SOC group. The negative conversion rate of SARS-CoV-2 within the first week in patients receiving arbidol tablets was significantly higher than that of the SOC group (70.3% [45/64] vs. 42.4% [14/33]; difference of conversion rate 27.9%; 95% confidence interval [CI], 7.7%–48.1%; P = 0.008). Compared to those in the SOC group, patients receiving arbidol tablets had a shorter duration of clinical recovery (median 7.0 days vs. 12.0 days; hazard ratio [HR]: 1.877, 95% CI: 1.151–3.060, P = 0.006), symptom of fever (median 3.0 days vs. 12.0 days; HR: 18.990, 95% CI: 5.350–67.410, P < 0.001), as well as hospitalization (median 12.5 days vs. 20.0 days; P < 0.001). Moreover, the addition of arbidol tablets to SOC led to more rapid normalization of declined blood lymphocytes (median 10.0 days vs. 14.5 days; P > 0.05). The most common adverse event in the arbidol tablets group was the elevation of transaminase (5/200, 2.5%), and no one withdrew from the study due to adverse events or disease progression. Conclusions: SOC plus arbidol tablets significantly increase the negative conversion rate of SARS-CoV-2 within the first week and accelerate the recovery of COVID-19 patients. During the treatment with arbidol tablets, we find no significant serious adverse events. Trial registration: Chinese Clinical Trial Registry, NCT04260594, www.clinicaltrials.gov/ct2/show/NCT04260594?term=NCT04260594&draw=2&rank=1

https://doi.org/10.1097/cm9.0000000000002104

A trial of arbidol hydrochloride in adults with COVID-19

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Design and biological evaluation of novel BF-30 analogs for the treatment of malignant melanoma

A trial of arbidol hydrochloride in adults with COVID-19