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Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel and highly pathogenic coronavirus and is the causative agent of COVID-19, an ongoing pandemic that has posed a serious threat to public health and global economy. Thus, there is a pressing need for therapeutic interventions that target essential viral proteins and regulate virus spread and replication. To invade the host cell, the receptor-binding domain (RBD) of SARS-CoV-2 Spike protein binds to the host cell's ACE2 receptor, followed by cleavage events that allow the Spike protein to fuse with the host cell membrane. Thus, the essential role of Spike protein in ACE2 receptor binding and viral fusion makes it a prime target for therapeutic interventions. Method(s): We performed molecular docking and molecular dynamics (MD) simulation-based virtual screening against SARS-CoV-2 RBD/ACE2 interface using a commercial library of 93,835 drug-like compounds. Compounds with promising docking poses and scores were selected for further MD simulation refinement, from which ten lead compounds were identified. Antiviral potencies of ten lead compounds were evaluated against lentiviral vectors pseudotyped with SARS-CoV-2 Spike to down select to a single lead compound, SAI4. ELISA-based assays were employed to determine the binding affinities of SAI4 to recombinant SARS-CoV-2 RBD. Antiviral potential of SAI4 was validated against genuine SARS-CoV-2 in a BSL3 setting. Result(s): We identified SAI4 as a candidate small molecule, which inhibited SARS-CoV-2 pseudovirus entry with IC50 value of ~18 muM. We determined that SAI4 binds RDB with a Kd of ~20 muM. Using cells engineered to express ACE2 and cells that express physiological levels of ACE2, we found that SAI4 inhibited SARS-CoV-2 pseudovirus entry at both engineered and physiological ACE2 levels. We validated the antiviral potential of SAI4 against genuine SARS-CoV-2 and HCoV-NL63. Lastly, we demonstrated antiviral potential of SAI4 against four SARS-CoV-2 variants of concern (alpha, beta, gamma, and delta). Conclusion(s): Using virtual screening, we identified SAI4 as the promising hit compound which displayed inhibitory activities against SARS-CoV-2 entry and its four variants of concern. Thus, our study will pave the way for further development of small molecules for therapeutic targeting of SARS-CoV-2 entry to combat the COVID-19 pandemic.
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Background: The unprecedented scale of the COVID-19 pandemic and rapid evolution of SARS-CoV-2 variants underscores the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (Mpro) is an essential viral enzyme required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir (PBI-0451) is a novel Mpro inhibitor currently completing phase 2 clinical trial. Here we describe the mechanism of action, broad activity against SARS-CoV-2 clinical isolates, combination studies with other SARS-CoV-2 inhibitors and favorable resistance profile of pomotrelvir. Method(s): The kinetic parameters of pomotrelvir Mpro inhibition and its interaction with nirmaltrevir were determined in a kinetic protease assay. The IC50s of pomotrelvir on mutant Mpro proteins were measured in an endpoint Mpro assay. Combination studies of pomotrelvir with remdesivir and molnupiravir were carried out in A549-hACE2 cells infected with SARS-CoV-2 NLuc virus. Activity against SARS-CoV-2 clinical variants was assessed by infection of A549-ACE2-TMPRSS2 cells followed by immunostaining of the viral nucleocapsid protein. Result(s): Pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 Mpro (Ki =2.7 nM). Binding of pomotrelvir and the Mpro inhibitor nirmatrelvir to the active site is mutually exclusive. In the SARS-CoV-2 NLuc assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. When the effect of Mpro substitutions previously selected in a resistance study of pomotrelvir were analyzed in an enzyme assay, only Mpro-N133H showed a significant increase in IC50 (45-fold). The catalytic efficiency of Mpro-N133H is reduced by 10-fold and the recombinant virus SARSCoV-2 (WA1) -N133H is not viable, suggesting that N133H has lower replicative fitness. Lastly, pomotrelvir exhibits broad activity against all SARS-CoV-2 clinical isolates tested to date, including five omicron variants. Conclusion(s): PBI-0451 is a potent competitive inhibitor of SARS-CoV-2 Mpro and is broadly active against SARS-CoV-2 clinical isolates including omicron variants. Results from inhibitor interaction studies support the potential combination of pomotrelvir with remdesivir and molnupiravir but not nirmatrelvir. Enzymatic characterization of in vitro selected pomotrelvir resistant variants indicates they either confer no resistance or have reduced fitness.
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Background: Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic initiation factor 4A (eIF4A), a host RNA helicase required for SARS-CoV-2 replication. Zotatifin selectively inhibits translation of ribonucleic acids (RNAs) containing specific short polypurine motifs in their 5-prime (5') regions. Two such highly conserved motifs are found in the SARS-CoV-2 genome. Zotatifin is currently being evaluated in a Phase 1b dose escalation study in 36 patients with mild to moderate COVID disease. In this in vitro study, we evaluated the selectivity of zotatifin's inhibition of SARS-CoV-2 translation, the antiviral activity of zotatifin alone against different human coronaviruses and the antiviral activity of zotatifin in combination with other antivirals against SARSCoV-2. Method(s): The selectivity of zotatifin for viral translation was evaluated in a cell-based reporter assay wherein luciferase translation was driven by 5'-sequences from SARS-CoV-2 or tubulin, a housekeeping gene. The antiviral activity of zotatifin was evaluated against SARS-CoV-1, SARS-CoV-2 variants (Wash/1/2020 (ancestral), delta, omicron BA.2), MERS-CoV and HCoV-299E in primary or established cell lines using cytopathic effect or infectious virus as endpoints. The antiviral activity of zotatifin in combination with remdesivir, N-hydroxycytidine (NHC;active nucleoside analogue metabolite of molnupiravir), nirmatrelvir, baricitinib or sotrovimab was evaluated against SARS-CoV-2 and analyzed by the method of Pritchard and Shipman. Result(s): Zotatifin inhibited the translation of the SARS-CoV-2 luciferase reporter construct with a mean IC50 of 3 nM and was ~14-fold less potent in inhibiting the tubulin reporter construct. Zotatifin potently inhibited the replication of all human coronaviruses tested with 50% effective concentrations (EC50s) ranging from 0.016 to 37.3 nM. The 50% cytotoxic concentration (CC50) value for zotatifin was 250 to >100,000 nM, yielding selectivity indices of 7 to >6250. Zotatifin was ~20 to >100-fold more potent than remdesivir, nirmatrelvir or NHC (figure) and demonstrated additive interactions when combined with remdesivir, NHC, nirmatrelvir, baricitinib or sotrovimab in vitro. Conclusion(s): The potent broad-spectrum activity of zotatifin against a variety of human coronaviruses and additive activity when combined with different anti-SARS-CoV-2 antivirals highlight the advantages of eIF4A as a target and warrant further evaluation in human clinical trials.
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Background: The continued emergence of severe acute respiratory syndrome coronaviruses (SARS-CoVs) and recent explosion of the SARS-CoV-2 pandemic highlights the need for broad and potent antibody recognition and understanding the contexts in which they may develop. Antibodies with cross reactivity across SARS lineages may be of particular value in preparing for future outbreaks of new sarbecoviruses. Method(s): We isolated monoclonal antibodies (mAbs) from an individual 60-days post-vaccination, 30-days post Delta-infection. Reconstructed antibodies were screened for binding to a panel of prefusion-stabilized Spike trimers from SARS-CoV-2 and other beta-coronaviruses using enzyme-linked immunosorbent assay (ELISA). Neutralization potency and breadth was assessed using a spike-pseudotyped lentivirus neutralization assay. Additionally, epitope and escape mutant profiling was conducted by deep mutational scanning (DMS) to identify mutations that affect antibody binding. Lastly, binding breadth was further evaluated using a yeast display library of RBDs from SARS-CoV-2 variants and related sarbecoviruses. Result(s): We identified several SARS-CoV-2-specific mAbs that neutralized SARS-CoV-2 variants of concern (VOCs) and SARS-CoV-1. Notably, two of these mAbs (C68.61 and C68.185) neutralized SARS-CoV-1 with an IC50 = 307 and 139 ng/mL (respectively) that is similar to or better than the potency of S309 (IC50 = 206 ng/mL) and CR3022 (IC50 = 981 ng/mL), which are mAbs isolated from individuals with SARS-CoV-1 infections. C68.61 also neutralized all Omicron VOCs tested and retained neutralization activity against currently circulating variants BQ1.1 (IC50=790 ng/ml) and XBB (IC50=590 ng/ml). Key C68.61 mAbescape mutations identified by DMS in the Omicron BA.2 background yeast display library included sites K462, E465, R466, and I468, which are conserved sites across all VOCs and SARS-CoV-1. The isolated mAbs displayed crossreactive binding to RBDs from diverse SARS-CoV-1-related CoVs and African and European sarbecovirus isolates as well as SARS-CoV-2 VOCs. Conclusion(s): Here we describe mAbs from a SARS-CoV-2-infected individual that bound and neutralized both SARS-CoV-2 and SARS-CoV-1, including one that showed breadth across recent VOCs. Given their breadth, these SARS-CoV-2 cross-reactive mAbs may be robust to viral escape and thus could contribute to therapeutic efforts. In addition, these mAbs displayed broad cross-reactive activity across sarbecoviruses and may be beneficial against future spillover events.
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Background: SARS-CoV-2 Omicron subvariants are highly resistant to vaccineinduced immunity and therapeutic monoclonal antibodies. We previously reported anti-SARS-CoV-2 spike alpaca nanobodies (VHHs) P86 and P17 that potently neutralize the wild type and VOCs from Alpha to Omicron BA.1 and BA.2, but not Omicron subvariants after that such as BA.4/5. Thus, we tried to establish a new VHH that can neutralize all the variants including BA.4/5. Method(s): We developed VHH trimers and heterodimers based on the structural and computational analysis of Delta spike-immunized alpaca VHH library. We tested representative VHHs against SARS-CoV-2 spike by pseudovirus assays and generated VHH heterodimers. We further obtained Cryo-EM structure of Spike trimer and VHH monomer or heterodimer. Result(s): First, we generated series of P86 mutants to counteract L452R mutation in Delta or Omicron BA.5 subvariants and found that P86 R45L was most potent against D614G with an IC50 of 0.03 mug/mL. From the Delta spike-immunized VHH library, we also identified that homo-trimer of a new clone P559 neutralized SARS-CoV-2 Delta and Omicron BA.5 variants with an IC50 of 0.077 and 0.54 mug/mL, respectively. We finally generated P559-R45L heterodimer that neutralized all the variants so far including Omicron BA.5 with an IC50 of 0.39 mug/mL. Cryo-EM structure revealed that three molecules of P559- R45L heterodimer bridged two RBD molecules in the spike trimer and stabilized spike timers with RBD in the up conformation. Conclusion(s): We developed VHH P559-R45L heterodimer that potently neutralized all the variants including Omicron subvariants through unique structural interaction.
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Background: While remarkable and rapid progress was made in fighting the SARS-CoV-2 pandemic with vaccines and therapeutic antibodies, these approaches were quickly compromised by viral evolution. Therapeutic monoclonal antibodies (mAbs) that were once authorized for clinical use, which all target the receptor binding domain (RBD), are no longer effective against current variants of concern (VOCs) due to mutations in this region of Spike. Thus, to achieve durable protection against SARS-CoV-2, novel mAbs need to show breadth and potency across VOCs and target epitopes that are more constrained. Method(s): mAbs from an individual who had a breakthrough Delta VOC infection after vaccination were isolated from Spike-specific memory B cells. mAbs were assessed for binding affinity and neutralization potency using Spike-pseudotyped lentivirus (PSV) and live SARS-CoV-2 virus neutralization assays. Epitopes were mapped using deep mutational sequencing (DMS) and structural-based methods. Result(s): Three novel mAbs (C68.3, C68.13, C68.59) demonstrated binding breadth to Spikes from various VOCs including Omicron VOCs despite that C68 had not yet been exposed to Omicron. These mAbs potently neutralized the Wuhan-Hu-1 vaccine and Delta strains (IC50 = 9-61ng/mL), and early Omicron strains BA.1, BA.2, BA.5 (IC50 = 12-149 ng/mL). C68.3 and C68.59 retained potency against recent VOCs BQ.1.1 and XBB (IC50 = 121-122 ng/mL and 56-82 ng/mL, respectively) in the PSV assay. Similar neutralization activity was observed in the live virus assay. The potency of these mAbs was greater against Omicron VOCs than all but one of the mAbs previously authorized for treatment and they showed greater breadth. The mAbs target distinct epitopes on the Spike glycoprotein, two in the RBD (C68.3, C68.13) and one in an invariant region downstream of RBD in subdomain 1 (SD1) (C68.59). Structural analysis of C68.59 Fab binding to Spike trimer revealed significant allosteric changes to regions of Spike outside of the epitope in the S2 unit. Finally, DMS escape pathways showed these mAbs target regions highly conserved across VOCs that are also functionally constrained, suggesting escape could incur a fitness cost. Conclusion(s): Overall, these mAbs are novel in their breadth across VOCs and include a potent mAb targeting a rare epitope outside of the RBD in SD1. These mAbs focus on diverse, functionally constrained regions in Spike making them candidates for development as combination therapeutics with good durability against future VOCs.
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Objectives: In this study, we developed angiotensin-converting enzyme 2 (ACE2)-specific, peptide-derived 68Ga- and 18F-labeled radiotracers, motivated by the hypotheses that ACE2 is an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and that modulation of ACE2 in coronavirus disease 2019 (COVID-19) drives severe organ injury. Our current efforts are focusing on broader dissemination of ACE2-targeted PET radiotracers based on chelation of [18F]AlF enabling advanced murine and potentially human studies. Method(s): A series of NOTA-conjugated peptides derived from the known ACE2 inhibitor DX600 were synthesized, with variable linker identity. Since DX600 bears 2 cystine residues, both linear and cyclic peptides were studied. An ACE2 inhibition assay was used to identify lead compounds, which were labeled with 68Ga and 18F-AlF to generate the corresponding peptide radiotracers (68Ga-NOTA-PEP). The most potent 68Ga and 18F-AlF DX600 derivatives were subsequently studied in a humanized ACE2 (hACE2) transgenic model. Result(s): Cyclic DX-600-derived peptides had markedly lower half-maximal inhibitory concentrations than their linear counterparts. The 3 cyclic peptides with triglycine, aminocaproate, and polyethylene glycol linkers had calculated half-maximal inhibitory concentrations similar to or lower than the parent DX600 molecule. Peptides were readily labeled with 68Ga and 18F-AlF, and the biodistribution of both tracers was determined in an hACE2 transgenic murine cohort. Pharmacologic concentrations of coadministered NOTA-PEP (blocking) showed a significant reduction of 68Ga-NOTA-PEP4 signals in the heart, liver, lungs, and small intestine. Ex vivo hACE2 activity in these organs was confirmed as a correlate to in vivo results. The biodistribution of both tracers was similar, with apparent blocking observed in the lungs using the 18F-AlF peptide that needs to be verified via additional experiments. Conclusion(s): NOTA-conjugated cyclic peptides derived from the known ACE2 inhibitor DX600 retain their activity when N-conjugated for 68Ga or 18F-AlF chelation. In vivo studies in a transgenic hACE2 murine model using the lead tracer, 68Ga-NOTA-PEP4, showed specific binding in the heart, liver, lungs and intestine-organs known to be affected in SARS-CoV-2 infection. Blocking studies using the 18F-AlF labeled correlate showed modulation of PET signals in the normal lungs. These results suggest that 68Ga-NOTA-PEP4 or the 18F-AlF correlate could be used to detect organ-specific suppression of ACE2 in SARS-CoV-2-infected murine models and COVID-19 patients.Copyright © 2023 Southern Society for Clinical Investigation.
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Historically organometallic compounds have been used to cure certain diseases with limited applications. Although bismuth belongs to the category of heavy metals, many of its derivatives have found applications in modern drug discovery research, mainly because of its low toxicity and higher bioavailability. Being an eco-friendly mild Lewis acid, compounds having bismuth as a central atom are capable of binding several proteins in humans and other species. Bismuth complexes demonstrated antibacterial potential in syphilis, diarrhea, gastritis, and colitis. Apart from antibacterial activities, bismuth compounds exhibited anticancer, antileishmanial, and some extent of antifungal and other medicinal properties. This article discusses major synthetic methods and pharmacological potentials of bismuth complexes exhibiting in vitro activity to significant clinical performance in a systematic and timely manner.Copyright © 2022 Elsevier Ltd
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Ferula asafoetida is an endemic species in Iran and is rich in oleo-gum resin with high economic value in the world. One important application of F. assafoetida is its traditional use for the management of respiratory ailments. The aim of this review was to collect papers dealing with F. asafoetida oleo-gum resin in respiratory tract's diseases in modern medicine. For preparing the manuscript the scientific databases (Google scholar, PubMed, Springer, Science Direct, Magiran), books, thesis, etc. were searched using the keywords of "Ferula asafoetida", "Ferula scorodesma", "Scorodesma foetida", "Northex asafoetida" plus "respiratory tract", "respiratory disorder" "infection", "cough", "trachea", "traditional medicine" up to Feb 2022 and the collected data were sum-marized, analyzed, and discussed. The results of the investigation confirmed the traditional belief on the efficacy of Ferula asafoetida in the treatment of respiratory viral infection (Coronavirus, influ-enza), cigarette smoking, asthma, cough and cancer, but most studies were limited to in vitro. There was only one registered randomized, blinded, placebo controlled clinical trial for 300 mg F. asafoet-ida aqueous extract capsules (three times a day for 14 days) on 40 patients with COVID-19 without any published results. Although, the studies implied the efficacy of F. asafoetida in the treatment of respiratory treatments, but design large clinical studies for evaluating its efficacy and safety is essential in future investigations.Copyright © 2023 Bentham Science Publishers.
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Continuous effort is dedicated to clinically and computationally discovering potential drugs for the novel coronavirus-2. Computer-Aided Drug Design CADD is the backbone of drug discovery, and shifting to computational approaches has become necessary. Quantitative Structure–Activity Relationship QSAR is a widely used approach in predicting the activity of potential molecules and is an early step in drug discovery. 3-chymotrypsin-like-proteinase 3CLpro is a highly conserved enzyme in the coronaviruses characterized by its role in the viral replication cycle. Despite the existence of various vaccines, the development of a new drug for SARS-CoV-2 is a necessity to provide cures to patients. In the pursuit of exploring new potential 3CLpro SARS-CoV-2 inhibitors and contributing to the existing literature, this work opted to build and compare three models of QSAR to correlate between the molecules' structure and their activity: IC50 through the application of Multiple Linear Regression(MLR), Support Vector Regression(SVR), and Particle Swarm Optimization-SVR algorithms (PSO-SVR). The database contains 71 novel derivatives of ML300which have proven nanomolar activity against the 3CLpro enzyme, and the GA algorithm obtained the representative descriptors. The built models were plotted and compared following various internal and external validation criteria, and applicability domains for each model were determined. The results demonstrated that the PSO-SVR model performed best in predictive ability and robustness, followed by SVR and MLR. These results also suggest that the branching degree 6 had a strong negative impact, while the moment of inertia X/Z ratio, the fraction of rotatable bonds, autocorrelation ATSm2, Keirshape2, and weighted path of length 2 positively impacted the activity. These outcomes prove that the PSO-SVR model is robust and concrete and paves the way for its prediction abilities for future screening of more significant inhibitors' datasets. © 2023, The Author(s) under exclusive licence to Associação Brasileira de Engenharia Química.
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Aim: To develop a simple, inexpensive antiviral screening assay, applicable to SARS-CoV-2, using a plate-based bioassay approach to assess the in-vitro activity of compounds against HCoV-OC43. Background(s): Despite the successful deployment of vaccines against SARS-CoV-2 there remains a need for effective antivirals for acute infection treatment. A distinct problem facing the search for new anti-coronavirus compounds is the cost of antiviral screening, compounded by the biosecurity concerns of live SARSCoV- 2 culture. In concert with low pathogenic surrogate virus use, the resazurin reduction assay, which is often employed for compound cytotoxicity assessments can be employed for safe, rapid and inexpensive antiviral screening. Method(s): In-vitro cell based resazurin reduction assays were optimised using remdesivir as a control compound for the assessment of anti-HCoV-OC43 activity. Following optimisation, 246 purified natural compounds from the University of Western Australia's compound collection,were screened using the resazurin bioassay as a primary screen, under pre-treatment and cotreatment conditions. Five compounds, which demonstrated anti- HCoV-OC43 activity, were chosen for secondary screening with dose responses determined using qRT-PCR. Result(s): Primary screens of the 246 compounds using the resazurin bioassay identified five compounds with a relative viral inhibition >60% and a relative cell viability >70% (Table 1). The Z factor of the pre-treatment and co-treatment assays was >0.5 (average +/- SD;0.85 +/- 0.07, 0.91 +/- 0.03 respectively). Further dose response analysis of the top five compounds identified one compound with an IC50 value <10 muM. Conclusion(s): The method developed is an appropriate primary screening tool for the identification of novel compounds with anti-HCoV-OC43 activity.Copyright © 2023 Southern Society for Clinical Investigation.
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Background: Patients with Inflammatory bowel disease (IBD) receiving anti-TNF or JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the currently dominant Omicron BA.4/5 variants. Method(s): We prospectively recruited 329 adults (68 healthy controls (HC) and 261 IBD) who had received three doses of COVID-19 vaccine at nine UK centres. The IBD population was established (>12 weeks therapy) on either thiopurine (n=60), infliximab (IFX) (n=43), thiopurine and IFX combination (n=46), ustekinumab (n=43), vedolizumab (n=46) or tofacitinib (n=23). Pseudoneutralisation assays were performed and the half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARSCoV-2 neutralising response against wild-type (WT) virus and the BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, ethnicity, vaccine type and age. Result(s): Heterologous (two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both WT SARS-CoV-2 virus and the BA.4/5 variants in HCs and IBD (fig 1). Antibody titres against BA.4/5 were significantly lower than antibodies against WT virus in both groups (Geometric Mean Ratio (GMR) [95% CI], 0.11 [0.09, 0.15], P<0.0001 in healthy participants;GMR 0.07 [0.06, 0.08], P<0.0001 in IBD patients). Multivariable models showed that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in IBD patients on IFX (GMR 0.44 [0.20, 0.97], P=0.042), IFX and thiopurine combination (GMR 0.34 [0.15, 0.77], P=0.0098) or tofacitinib (GMR 0.37 [0.15, 0.92], P=0.032), but not in patients on thiopurine monotherapy, ustekinumab or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against WT and BA.4/5 (P<0.05). Conclusion(s): A third dose of COVID-19 vaccine based on the WT spike glycoprotein boosts neutralising antibody titres in patients with IBD. However, responses are lower against the currently dominant variant BA.4/5, particularly in patients taking anti-TNF or JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed IBD patients may receive additional benefit from bivalent vaccine boosters which target Omicron variants. .
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Background: Phytochemicals and their derivatives/analogues represent over 50% of the current medicines worldwide in clinical use. Despite a significant contribution to the total bioactive natural plant products, aquatic plants are underestimated, and several species are extinct and in the endangered list. Objective(s): The aim of this review article is to draw the attention of common people and scientists toward a few important contributions of the aquatic plants to natural product chemistry and drug discovery by highlighting the chemical and pharmaceutical aspects of the same. Method(s): The presented data were collected and selected from the literature obtained by an online search for the ethnomedicinal properties, biological activities and bioactive chemical constituents of aquatic plants using Google Scholar, PubMed and Scifinder chemical abstract service. Result(s): The selected literature data revealed that the extract and compounds isolated from several aquatic plants possess significant biological/pharmaceutical properties. For example, the alpha-asarone (24) and asiatic acid (33) isolated from Acorus calamus and Centella asiatica, respectively, exhibited significant neuroprotective effects in vitro and in vivo. The cripowellin A (59), cripowellin C (60), cripowellin B (61) and cripowellin D (62), isolated from Crinum erubescens, exhibited potent antiplasmodial and antiproliferative activities with half maximal inhibitory concentration (IC50) in nanomolar range (11-260 nM). Several other alkaloids from different Crinum species have also shown anticancer properties against different cancer cell lines with IC50 value <5 microM. Alkaloids and resin glycosides, isolated from different Ipomoea species, have displayed significant psychotropic, psychotomimetic, anticancer, and antibacterial activities with IC50 value <5 microM. Conclusion(s): The aquatic plants play a significant role in the discovery of bioactive natural products. Although several biological activities and bioactive compounds have been reported from these plants, further assessment and scientific validation of most of their traditional usages still need to be done. There are several other similar species that are underestimated and not much explored. Many aquatic plants, such as Ipomoea carnea Jacq., Juncus lomatophyllus Spreng., Commelina benghalensis Linn, Gunnera perpensa L., Scirpus maritimus L. and Mentha longifolia (L.) L., may be considered for further evaluation. In addition to these, one should not undermine the potential of Crinum macowanii for COVID-19 pathogenesis, as its chemical constituent lycorine has shown significant SARS-CoV-2 inhibitory potential (EC50, 0.3 muM;SI >129). Furthermore, most rural communities are still using the wetland resources for their cultural, medicinal, economic, domestic, and agricultural needs. Hence, the conservation of aquatic plants and wetlands is an issue of great concern.Copyright © 2023 Bentham Science Publishers.
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The COVID-19 disease pandemic remains a significant global problem, resulting in hundreds of millions of cases and millions of deaths. The search for specific inhibitors of SARS-CoV-2 for the treatment of this infection remains relevant. Drugs such as Favipiravir and Molnupiravir, which exhibit specific antiviral activity against SARS-CoV-2, are already being used to treat patients. However, there is limited evidence of their effectiveness, especially against novel genetic variants of the COVID-19 pathogen. The aim of this study was to investigate the antiviral effect of these drugs using an in vitro experimental model of SARS-CoV-2 infection in Vero E6 cell culture and an animal model of infection using Syrian hamsters. It has been established that Molnupiravir has an inhibitory effect against variants of the SARS-CoV-2 with IC50 values from 16.51 to 7.88 microM in vitro, and reduces the infectious titer of the virus in the lungs of animals by ~1.5 Log10 in vivo, in while Favipiravir shows lower activity and severe toxicity. Dose selection and frequency of use remain unexplored.Copyright © 2022 Pirogov Russian National Research Medical University. All rights reserved.
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COVID-19 is a global pandemic caused by infection with the SARS-CoV-2 virus. Remdesivir, a SARS-CoV-2 RNA polymerase inhibitor, is the only drug to have received widespread approval for treatment of COVID-19. The SARS-CoV-2 main protease enzyme (MPro), essential for viral replication and transcription, remains an active target in the search for new treatments. In this study, the ability of novel thiazolyl-indazole derivatives to inhibit MPro is evaluated. These compounds were synthesized via the heterocyclization of phenacyl bromide with (R)-carvone, (R)-pulegone and (R)-menthone thiosemicarbazones. The binding affinity and binding interactions of each compound were evaluated through Schrodinger Glide docking, AMBER molecular dynamics simulations, and MM-GBSA free energy estimation, and these results were compared with similar calculations of MPro binding various 5-mer substrates (VKLQA, VKLQS, VKLQG) and a previously identified MPro tight-binder X77. From these simulations, we can see that binding is driven by residue specific interactions such as pi-stacking with His41, and S/pi interactions with Met49 and Met165. The compounds were also experimentally evaluated in a MPro biochemical assay and the most potent compound containing a phenylthiazole moiety inhibited protease activity with an IC50 of 92.9 muM. This suggests that the phenylthiazole scaffold is a promising candidate for the development of future MPro inhibitors.Copyright © 2022 The Authors
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Molecular docking and molecular dynamics aided virtual search of OliveNet™ directory identified potential secoiridoids that combat SARS-CoV-2 entry, replication, and associated hyperinflammatory responses. OliveNet™ is an active directory of phytochemicals obtained from different parts of the olive tree, Olea europaea (Oleaceae). Olive oil, olive fruits containing phenolics, known for their health benefits, are indispensable in the Mediterranean and Arabian diets. Secoiridoids is the largest group of olive phenols and is exclusive to the olive fruits. Functional food like olive fruits could help prevent and alleviate viral disease at an affordable cost. A systematized virtual search of 932 conformers of 78 secoiridoids utilizing Autodock Vina, followed by precision docking using Idock and Smina indicated that Nüzhenide oleoside (NZO), Oleuropein dimer (OED), and Dihydro oleuropein (DHO) blocked the SARSCoV-2 spike (S) protein-ACE-2 interface;Demethyloleuropein (DMO), Neo-nüzhenide (NNZ), and Nüzhenide (NZE) blocked the SARS-CoV-2 main protease (Mpro). Molecular dynamics (MD) simulation of the NZO-S-protein-ACE-2 complex by Desmond revealed stability during 50 ns. RMSD of the NZO-S-protein-ACE-2 complex converged at 2.1 Å after 20 ns. During MD, the interaction fractions confirmed multiple interactions of NZO with Lys417, a crucial residue for inhibition of S protein. MD of DMO-Mpro complex proved its stability as the RMSD converged at 1.6 Å. Analysis of interactions during MD confirmed the interaction of Cys145 of Mpro with DMO and, thus, its inhibition. The docking predicted IC50 of NZO and DMO was 11.58 and 6.44 μM, respectively. Molecular docking and dynamics of inhibition of the S protein and Mpro by NZO and DMO correlated well. Docking of the six-hit secoiridoids to IL1R, IL6R, and TNFR1, the receptors of inflammatory cytokines IL1β, IL6, and TNFα, revealed the anti-inflammatory potential except for DHO. Due to intricate structures, the secoiridoids violated Lipinski's rule of five. However, the drug scores of secoiridoids supported their use as drugs. The ADMET predictions implied that the secoiridoids are non-toxic and pose low oral absorption. Secoiridoids need further optimization and are a suitable lead for the discovery of anti-SARS-CoV-2 therapeutics. For the moment, olive secoiridoids presents an accessible mode of prevention and therapy of SARS-CoV-2 infection.
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Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)
ABSTRACT
Highly mutable pathogens pose daunting challenges for antibody design. The usual criteria of high potency and specificity are often insufficient to design antibodies that provide long-lasting protection. This is due, in part, to the ability of the pathogen to rapidly acquire mutations that permit them to evade the designed antibodies. To overcome these limitations, design of antibodies with a larger neutralizing breadth can be pursued. Such broadly neutralizing antibodies (bnAbs) should remain targeted to a specific epitope, yet show robustness against pathogen mutability, thereby neutralizing a higher number of antigens. This is particularly important for highly mutable pathogens, like the influenza virus and the human immunodeficiency virus (HIV). The protocol describes a method for computing the "breadth” of a given antibody, an essential aspect of antibody design. © 2023, Springer Science+Business Media, LLC, part of Springer Nature.
ABSTRACT
The global anxiety and economic crisis causes the deadly pandemic coronavirus disease of 2019 (COVID 19) affect millions of people right now. Subsequently, this life threatened viral disease is caused due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, morbidity and mortality of infected patients are due to cytokines storm syndrome associated with lung injury and multiorgan failure caused by COVID 19. Thereafter, several methodological advances have been approved by WHO and US-FDA for the detection, diagnosis and control of this wide spreadable communicable disease but still facing multi-challenges to control. Herein, we majorly emphasize the current trends and future perspectives of nano-medicinal based approaches for the delivery of anti-COVID 19 therapeutic moieties. Interestingly, Nanoparticles (NPs) loaded with drug molecules or vaccines resemble morphological features of SARS-CoV-2 in their size (60–140 nm) and shape (circular or spherical) that particularly mimics the virus facilitating strong interaction between them. Indeed, the delivery of anti-COVID 19 cargos via a nanoparticle such as Lipidic nanoparticles, Polymeric nanoparticles, Metallic nanoparticles, and Multi-functionalized nanoparticles to overcome the drawbacks of conventional approaches, specifying the site-specific targeting with reduced drug loading and toxicities, exhibit their immense potential. Additionally, nano-technological based drug delivery with their peculiar characteristics of having low immunogenicity, tunable drug release, multidrug delivery, higher selectivity and specificity, higher efficacy and tolerability switch on the novel pathway for the prevention and treatment of COVID 19. © 2022 The Author(s)