Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L
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ABSTRACT:
SUBMITTER: Ashhurst A
PROVIDER: S-EPMC8577376 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro and PLpro. We demonstrate that gallinamide A directly interacts with cathepsin L in cells, and together with two lead analogues potently inhibits SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. However, in an in vivo mouse model of infection, gallinamide A did not reduce viral load in the lung tissue, possibly due to compensatory viral entry mechanisms. In support of this, in TMPRSS2-overexpressing cells gallinamide A had reduced anti-viral activity, but when combined with a TMPRSS2 inhibitor synergistically improved inhibition of viral entry. The data highlights the potential of cathepsin L as a COVID-19 antiviral drug target, and the likely necessity to inhibit multiple routes of viral entry routes to achieve therapeutic efficacy.
2022-02-17 | PXD027300 | Pride
Project description:Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a dreaded pandemic in lack of specific therapeutic agent. SARS-CoV-2 Mpro, an essential factor in viral pathogenesis, is recognized as a prospective therapeutic target in drug discovery against SARS-CoV-2. To tackle this pandemic, Food and Drug Administration-approved drugs are being screened against SARS-CoV-2 Mpro via in silico and in vitro methods to detect the best conceivable drug candidates. However, identification of natural compounds with anti-SARS-CoV-2 Mpro potential have been recommended as rapid and effective alternative for anti-SARS-CoV-2 therapeutic development. Thereof, a total of 653 natural compounds were identified against SARS-CoV-2 Mpro from NP-lib database at MTi-OpenScreen webserver using virtual screening approach. Subsequently, top four potential compounds, i.e. 2,3-Dihydroamentoflavone (ZINC000043552589), Podocarpusflavon-B (ZINC000003594862), Rutin (ZINC000003947429) and Quercimeritrin 6"-O-L-arabinopyranoside (ZINC000070691536), and co-crystallized N3 inhibitor as reference ligand were considered for stringent molecular docking after geometry optimization by DFT method. Each compound exhibited substantial docking energy >-12 kcal/mol and molecular contacts with essential residues, including catalytic dyad (His41 and Cys145) and substrate binding residues, in the active pocket of SARS-CoV-2 Mpro against N3 inhibitor. The screened compounds were further scrutinized via absorption, distribution, metabolism, and excretion - toxicity (ADMET), quantum chemical calculations, combinatorial molecular simulations and hybrid QM/MM approaches. Convincingly, collected results support the potent compounds for druglikeness and strong binding affinity with the catalytic pocket of SARS-CoV-2 Mpro. Hence, selected compounds are advocated as potential inhibitors of SARS-CoV-2 Mpro and can be utilized in drug development against SARS-CoV-2 infection.
| S-EPMC7929395 | biostudies-literature
Project description:Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.
| S-EPMC5337940 | biostudies-literature
Project description:The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide for almost 2 years. It starts from viral adherence to host cells through an interaction between spike glycoprotein 1 (S1) containing a receptor-binding domain (RBD) and human angiotensin-converting enzyme-2 (ACE2). One of the useful strategies to prevent SARS-CoV-2 infection is to inhibit the attachment of RBD to ACE2. Therefore, the current work proposed potent peptides against SARS-CoV-2 infection by carrying out MM-PBSA calculation based on the binding of 52 antiviral peptides (AVPs) to RBD. Considering the binding free energies of AVPs to RBD, cyanovirin-N (CV-N) showed the strongest RBD binding affinity among 52 AVPs. Upon structural analysis of RBD complex with CV-N, it was observed that 12 of the 13 key residues of RBD binding to ACE2 were hijacked by CV-N. CV-N bound to RBD at a smaller affinity of 14.9 nM than that of ACE2 and inhibited the recruitment of S1 to human alveolar epithelial cells. Further analysis revealed that CV-N suppressed SARS-CoV-2 S pseudovirion infection with a half-maximal inhibitory concentration (IC50) of 18.52 μg/mL. This study demonstrated a drug screening for AVPs against SARS-CoV-2 and discovered a peptide with inspiring antiviral properties, which provided a promising strategy for the COVID-19 therapeutic approach.
| S-EPMC8435140 | biostudies-literature
Project description:Cepharanthine (CEP) is a natural biscoclaurine alkaloid of plant origin and was recently demonstrated to have anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) activity. In this study, we evaluated whether natural analogues of CEP may act as potential anti-coronavirus disease 2019 drugs. A total of 24 compounds resembling CEP were extracted from the KNApSAcK database, and their binding affinities to target proteins, including the spike protein and main protease of SARS-CoV-2, NPC1 and TPC2 in humans, were predicted via molecular docking simulations. Selected analogues were further evaluated by a cell-based SARS-CoV-2 infection assay. In addition, the efficacies of CEP and its analogue tetrandrine were assessed. A comparison of the docking conformations of these compounds suggested that the diphenyl ester moiety of the molecules was a putative pharmacophore of the CEP analogues.
| S-EPMC8727928 | biostudies-literature
Project description:SARS-CoV-2, the virus causing COVID-19, is a single-stranded RNA virus belonging to the order Nidovirales, family Coronaviridae, and subfamily Coronavirinae. SARS-CoV-2 entry to cellsis initiated by the binding of the viral spike protein (S) to its cellular receptor. The roles of S protein in receptor binding and membrane fusion makes it a prominent target for vaccine development. SARS-CoV-2 genome sequence analysis has shown that this virus belongs to the beta-coronavirus genus, which includes Bat SARS-like coronavirus, SARS-CoV and MERS-CoV. A vaccine should induce a balanced immune response to elicit protective immunity. In this review, we compare and contrast these three important CoV diseases and how they inform on vaccine development.
| S-EPMC7872062 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is a life-threatening malignant tumor with high incidence rate. Despite great progress, there are still many GC sufferers that cannot benefit from the existing anti-GC treatments. Therefore, it is still necessary to develop novel medicines against GC. Emetine, a natural small molecule isolated from Psychotria ipecacuanha, has been broadly used for medicinal purposes including cancer treatment. Here, we conducted a comprehensive study on the anti-GC effects of emetine and the related mechanisms of action.MethodsThe cell viability was evaluated by MTT and colony formation assay. Cellular proliferation and apoptosis were analyzed by edu incorporation assay and Annexin V-PI staining, respectively. Moreover, wound healing assay and transwell invasion assay were conducted to detect cell migration and invasion after treatment with emetine. To elucidate the molecular mechanism involved in the anti-GC effects of emetine, RNA sequencing and functional enrichment analysis were carried out on MGC803 cells. Then, the western blot analysis was performed to further verify the anti-GC mechanism of emetine. In vivo anti-tumor efficacy of emetine was evaluated in the MGC803 xenograft model.ResultsMTT and colony formation assay exhibited a strong potency of emetine against GC cell growth, with IC50 values of 0.0497 μM and 0.0244 μM on MGC803 and HGC-27 cells, respectively. Further pharmacodynamic studies revealed that emetine restrained the growth of GC cells mainly via proliferation inhibition and apoptosis induction. Meanwhile, emetine also had the ability to block GC cell migration and invasion. The results of RNA sequencing and western blot showed that emetine acted through regulating multiple signaling pathways, including not only MAPKs and Wnt/β-catenin signaling axes, but also PI3K/AKT and Hippo/YAP signaling cascades that were not found in other tumor types. Notably, the antitumor efficacy of emetine could also be observed in MGC803 xenograft models.ConclusionOur data demonstrate that emetine is a promising lead compound and even a potential drug candidate for GC treatment, deserving further structural optimization and development.
| S-EPMC10027284 | biostudies-literature
Project description:Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b-1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. The key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a-4g). All bis-indole compounds synthesized were evaluated against the Mycobacterium tuberculosis strain H37Rv, and 1a was found to display excellent activity (IC?? 0.24 µM).
| S-EPMC4012461 | biostudies-literature
Project description:Tannins are polyphenols enriched in wood, bark, roots, leaves, seeds and fruits of a variety of plants. Over the last two decades, there has been an increasing interest in understanding the biological functions of tannins and their applications as antioxidants, anticancer drugs, and food additives. Since the outbreak of the COVID-19 pandemic, much effort has been devoted to finding an expedient cure. Tannins have been put forward as having possible anti-COVID-19 properties; however, owing to the profuse nature of the structurally diverse derivatives of tannins, the tannin species in the family associated with an indication of anti-COVID-19 have been poorly defined, compounded by frequent terminology misnomers. This article reviews the tannin family in fruits and the current knowledge about the activities of the compounds with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It will aid molecular and cellular biologists in developing natural anti-viral chemicals as means of overcoming the current and future pandemics.
| S-EPMC9305278 | biostudies-literature
Project description:Dysregulated immune responses contribute to the excessive and uncontrolled inflammation observed in severe COVID-19. However, how immunity to SARS-CoV-2 is induced and regulated remains unclear. Here we uncover a role of the complement system in the induction of innate and adaptive immunity to SARS-CoV-2. Complement rapidly opsonizes SARS-CoV-2 particles via the lectin pathway. Complement-opsonized SARS-CoV-2 efficiently induces type-I interferon and pro-inflammatory cytokine responses via activation of dendritic cells, which are inhibited by antibodies against the complement receptors (CR) 3 and 4. Serum from COVID-19 patients, or monoclonal antibodies against SARS-CoV-2, attenuate innate and adaptive immunity induced by complement-opsonized SARS-CoV-2. Blocking of CD32, the FcγRII antibody receptor of dendritic cells, restores complement-induced immunity. These results suggest that opsonization of SARS-CoV-2 by complement is involved in the induction of innate and adaptive immunity to SARS-CoV-2 in the acute phase of infection. Subsequent antibody responses limit inflammation and restore immune homeostasis. These findings suggest that dysregulation of the complement system and FcγRII signaling may contribute to severe COVID-19.
| S-SCDT-10_1038-S44318-024-00061-0 | biostudies-other