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1.
J Chem Inf Model ; 63(11): 3601-3613, 2023 06 12.
Article in English | MEDLINE | ID: covidwho-20232259

ABSTRACT

The SARS-CoV-2 main protease (Mpro) is a crucial enzyme for viral replication and has been considered an attractive drug target for the treatment of COVID-19. In this study, virtual screening techniques and in vitro assays were combined to identify novel Mpro inhibitors starting from around 8000 FDA-approved drugs. The docking analysis highlighted 17 promising best hits, biologically characterized in terms of their Mpro inhibitory activity. Among them, 7 cephalosporins and the oral anticoagulant betrixaban were able to block the enzyme activity in the micromolar range with no cytotoxic effect at the highest concentration tested. After the evaluation of the degree of conservation of Mpro residues involved in the binding with the studied ligands, the ligands' activity on SARS-CoV-2 replication was assessed. The ability of betrixaban to affect SARS-CoV-2 replication associated to its antithrombotic effect could pave the way for its possible use in the treatment of hospitalized COVID-19 patients.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Drug Repositioning , Ligands , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation
2.
Viruses ; 15(5)2023 05 09.
Article in English | MEDLINE | ID: covidwho-20237088

ABSTRACT

During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/metabolism , Pandemics , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/metabolism , Drug Repositioning/methods
3.
Eur J Med Chem ; 244: 114853, 2022 Dec 15.
Article in English | MEDLINE | ID: covidwho-2301653

ABSTRACT

SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (Mpro) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of Mpro, exploiting the PADAM oxidation route. The reported compounds showed µM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 Mpro. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 Mpro in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of Mpro. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS Mpro where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Humans , Coronavirus 3C Proteases , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , Viral Nonstructural Proteins , Cysteine Endopeptidases/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Molecular Docking Simulation
4.
Eur J Med Chem ; 253: 115311, 2023 May 05.
Article in English | MEDLINE | ID: covidwho-2304178

ABSTRACT

Despite the approval of vaccines, monoclonal antibodies and restrictions during the pandemic, the demand for new efficacious and safe antivirals is compelling to boost the therapeutic arsenal against the COVID-19. The viral 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for replication with high homology in the active site across CoVs and variants showing an almost unique specificity for Leu-Gln as P2-P1 residues, allowing the development of broad-spectrum inhibitors. The design, synthesis, biological activity, and cocrystal structural information of newly conceived peptidomimetic covalent reversible inhibitors are herein described. The inhibitors display an aldehyde warhead, a Gln mimetic at P1 and modified P2-P3 residues. Particularly, functionalized proline residues were inserted at P2 to stabilize the ß-turn like bioactive conformation, modulating the affinity. The most potent compounds displayed low/sub-nM potency against the 3CLpro of SARS-CoV-2 and MERS-CoV and inhibited viral replication of three human CoVs, i.e. SARS-CoV-2, MERS-CoV, and HCoV 229 in different cell lines. Particularly, derivative 12 exhibited nM-low µM antiviral activity depending on the virus, and the highest selectivity index. Some compounds were co-crystallized with SARS-CoV-2 3CLpro validating our design. Altogether, these results foster future work toward broad-spectrum 3CLpro inhibitors to challenge CoVs related pandemics.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Peptidomimetics , Humans , SARS-CoV-2 , Protease Inhibitors/chemistry , Peptidomimetics/pharmacology , Peptidomimetics/chemistry , X-Rays , Peptide Hydrolases , Antiviral Agents/chemistry
5.
EMBO Mol Med ; 15(5): e17580, 2023 05 08.
Article in English | MEDLINE | ID: covidwho-2259755

ABSTRACT

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir-an orally available inhibitor of the 3-chymotrypsin-like cysteine protease-has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using mouse models of SARS-CoV-2 infection, we show that nirmatrelvir administration blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Mice , Antibodies, Viral , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Lactams , Nitriles , Immunity
6.
Microbiol Spectr ; 11(1): e0251622, 2023 02 14.
Article in English | MEDLINE | ID: covidwho-2193556

ABSTRACT

SARS-CoV-2 infection is known to trigger an important inflammatory response, which has a major role in COVID-19 pathogenesis. In infectious and inflammatory contexts, the modulation of human endogenous retroviruses (HERV) has been broadly reported, being able to further sustain innate immune responses due to the expression of immunogenic viral transcripts, including double-stranded DNA (dsRNA), and eventually, immunogenic proteins. To gain insights on this poorly characterized interplay, we performed a high-throughput expression analysis of ~3,300 specific HERV loci in the peripheral blood mononuclear cells (PBMCs) of 10 healthy controls and 16 individuals being either convalescent after the infection (6) or retesting positive after convalescence (10) (Gene Expression Onmibus [GEO] data set GSE166253). Results showed that the exposure to SARS-CoV-2 infection modulates HERV expression according to the disease stage and reflecting COVID-19 immune signatures. The differential expression analysis between healthy control (HC) and COVID-19 patients allowed us to identify a total of 282 differentially expressed HERV loci (deHERV) in the individuals exposed to SARS-CoV-2 infection, independently from the clinical form. In addition, 278 and 60 deHERV loci that were specifically modulated in individuals convalescent after COVID19 infection (C) and patients that retested positive to SARS-CoV-2 after convalescence (RTP) as individually compared to HC, respectively, as well as 164 deHERV loci between C and RTP patients were identified. The identified HERV loci belonged to 36 different HERV groups, including members of all three classes. The present study provides an exhaustive picture of the HERV transcriptome in PBMCs and its dynamic variation in the presence of COVID-19, revealing specific modulation patterns according to the infection stage that can be relevant to the disease clinical manifestation and outcome. IMPORTANCE We report here the first high-throughput analysis of HERV loci expression along SARS-CoV-2 infection, as performed with peripheral blood mononuclear cells (PBMCs). Such cells are not directly infected by the virus but have a crucial role in the plethora of inflammatory and immune events that constitute a major hallmark of COVID-19 pathogenesis. Results provide a novel and exhaustive picture of HERV expression in PBMCs, revealing specific modulation patterns according to the disease condition and the concomitant immune activation. To our knowledge, this is the first set of deHERVs whose expression is dynamically modulated across COVID-19 stages, confirming a tight interplay between HERV and cellular immunity and revealing specific transcriptional signatures that can have an impact on the disease clinical manifestation and outcome.


Subject(s)
COVID-19 , Endogenous Retroviruses , Humans , Endogenous Retroviruses/genetics , Transcriptome , Leukocytes, Mononuclear , Convalescence , COVID-19/genetics , SARS-CoV-2/genetics
7.
Molecules ; 27(21)2022 Nov 03.
Article in English | MEDLINE | ID: covidwho-2099667

ABSTRACT

The SARS-CoV-2 non-structural protein 13 (nsp13) helicase is an essential enzyme for viral replication and has been identified as an attractive target for the development of new antiviral drugs. In detail, the helicase catalyzes the unwinding of double-stranded DNA or RNA in a 5' to 3' direction and acts in concert with the replication-transcription complex (nsp7/nsp8/nsp12). In this work, bioinformatics and computational tools allowed us to perform a detailed conservation analysis of the SARS-CoV-2 helicase genome and to further predict the druggable enzyme's binding pockets. Thus, a structure-based virtual screening was used to identify valuable compounds that are capable of recognizing multiple nsp13 pockets. Starting from a database of around 4000 drugs already approved by the Food and Drug Administration (FDA), we chose 14 shared compounds capable of recognizing three out of four sites. Finally, by means of visual inspection analysis and based on their commercial availability, five promising compounds were submitted to in vitro assays. Among them, PF-03715455 was able to block both the unwinding and NTPase activities of nsp13 in a micromolar range.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Humans , Drug Repositioning , RNA Helicases/metabolism , Viral Nonstructural Proteins/metabolism , DNA Helicases/metabolism , Antiviral Agents/pharmacology
8.
ACS Med Chem Lett ; 13(5): 855-864, 2022 May 12.
Article in English | MEDLINE | ID: covidwho-1947205

ABSTRACT

A selection of compounds from a proprietary library, based on chemical diversity and various biological activities, was evaluated as potential inhibitors of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in a phenotypic-based screening assay. A compound based on a 2-phenylquinoline scaffold emerged as the most promising hit, with EC50 and CC50 values of 6 and 18 µM, respectively. The subsequent selection of additional analogues, along with the synthesis of ad hoc derivatives, led to compounds that maintained low µM activity as inhibitors of SARS-CoV-2 replication and lacked cytotoxicity at 100 µM. In addition, the most promising congeners also show pronounced antiviral activity against the human coronaviruses HCoV-229E and HCoV-OC43, with EC50 values ranging from 0.2 to 9.4 µM. The presence of a 6,7-dimethoxytetrahydroisoquinoline group at the C-4 position of the 2-phenylquinoline core gave compound 6g that showed potent activity against SARS-CoV-2 helicase (nsp13), a highly conserved enzyme, highlighting a potentiality against emerging HCoVs outbreaks.

9.
Sci Data ; 9(1): 405, 2022 07 13.
Article in English | MEDLINE | ID: covidwho-1931428

ABSTRACT

Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Discovery , Drug Repositioning , Humans
10.
ACS Pharmacol Transl Sci ; 5(4): 226-239, 2022 Apr 08.
Article in English | MEDLINE | ID: covidwho-1852382

ABSTRACT

SARS-CoV-2 infection is still spreading worldwide, and new antiviral therapies are an urgent need to complement the approved vaccine preparations. SARS-CoV-2 nps13 helicase is a validated drug target participating in the viral replication complex and possessing two associated activities: RNA unwinding and 5'-triphosphatase. In the search of SARS-CoV-2 direct antiviral agents, we established biochemical assays for both SARS-CoV-2 nps13-associated enzyme activities and screened both in silico and in vitro a small in-house library of natural compounds. Myricetin, quercetin, kaempferol, and flavanone were found to inhibit the SARS-CoV-2 nps13 unwinding activity at nanomolar concentrations, while licoflavone C was shown to block both SARS-CoV-2 nps13 activities at micromolar concentrations. Mode of action studies showed that all compounds are nsp13 noncompetitive inhibitors versus ATP, while computational studies suggested that they can bind both nucleotide and 5'-RNA nsp13 binding sites, with licoflavone C showing a unique pattern of interaction with nsp13 amino acid residues. Overall, we report for the first time natural flavonoids as selective inhibitors of SARS-CoV-2 nps13 helicase with low micromolar activity.

11.
Front Public Health ; 10: 846115, 2022.
Article in English | MEDLINE | ID: covidwho-1753422

ABSTRACT

In December 2019, a novel coronavirus emerged in Wuhan, China, rapidly spreading into a global pandemic. Italy was the first European country to experience SARS-CoV-2 epidemic, and one of the most severely affected during the first wave of diffusion. In contrast to the general restriction of people movements in Europe, the number of migrants arriving at Italian borders via the Mediterranean Sea route in the summer of 2020 had increased dramatically, representing a possible, uncontrolled source for the introduction of novel SARS-CoV-2 variants. Importantly, most of the migrants came from African countries showing limited SARS-CoV-2 epidemiological surveillance. In this study, we characterized the SARS-CoV-2 genome isolated from an asymptomatic migrant arrived in Sardinia via the Mediterranean route in September 2020, in comparison with SARS-CoV-2 isolates arrived in Sicily through the Libyan migration route; with SARS-CoV-2 isolates circulating in Sardinia during 2020; and with viral genomes reported in African countries during the same summer. Results showed that our sequence is not phylogenetically related to isolates from migrants arriving in Sicily, nor to isolates circulating in Sardinia territory, having greater similarity to SARS-CoV-2 genomes reported in countries known for being sites of migrant embarkation to Italy. This is in line with the hypothesis that most SARS-CoV-2 infections among migrants have been acquired prior to embarking to Italy, possibly during the travel to or the stay in crowded Libyan immigrant camps. Overall, these observations underline the importance of dedicated SARS-CoV-2 surveillance of migrants arriving in Italy and in Europe through the Mediterranean routes.


Subject(s)
COVID-19 , Transients and Migrants , COVID-19/epidemiology , Genomics , Humans , Mediterranean Sea , SARS-CoV-2/genetics
12.
Front Microbiol ; 11: 628194, 2020.
Article in English | MEDLINE | ID: covidwho-1575310

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the coronavirus disease 2019 (COVID-19) pandemic, which started as a severe pneumonia outbreak in Wuhan, China, in December 2019. Italy has been the first European country affected by the pandemic, registering a total of 300,363 cases and 35,741 deaths until September 24, 2020. The geographical distribution of SARS-CoV-2 in Italy during early 2020 has not been homogeneous, including regions severely affected as well as administrative areas being only slightly interested by the infection. Among the latter, Sardinia represents one of the lowest incidence areas likely due to its insular nature. METHODS: Next-generation sequencing of a small number of complete viral genomes from clinical samples and their virologic and phylogenetic characterization was performed. RESULTS: We provide a first overview of the SARS-CoV-2 genomic diversity in Sardinia in the early phase of the March-May 2020 pandemic based on viral genomes isolated in the most inner regional hospital of the island. Our analysis revealed a remarkable genetic diversity in local SARS-CoV-2 viral genomes, showing the presence of at least four different clusters that can be distinguished by specific amino acid substitutions. Based on epidemiological information, these sequences can be linked to at least eight different clusters of infection, four of which likely originates from imported cases. In addition, the presence of amino acid substitutions that were not previously reported in Italian patients has been observed, asking for further investigations in a wider population to assess their prevalence and dynamics of emergence during the pandemic. CONCLUSION: The present study provides a snapshot of the initial phases of the SARS-CoV-2 infection in inner area of the Sardinia Island, showing an unexpected genomic diversity.

13.
Int J Mol Sci ; 22(21)2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1488616

ABSTRACT

After almost two years from its first evidence, the COVID-19 pandemic continues to afflict people worldwide, highlighting the need for multiple antiviral strategies. SARS-CoV-2 main protease (Mpro/3CLpro) is a recognized promising target for the development of effective drugs. Because single target inhibition might not be sufficient to block SARS-CoV-2 infection and replication, multi enzymatic-based therapies may provide a better strategy. Here we present a structural and biochemical characterization of the binding mode of MG-132 to both the main protease of SARS-CoV-2, and to the human Cathepsin-L, suggesting thus an interesting scaffold for the development of double-inhibitors. X-ray diffraction data show that MG-132 well fits into the Mpro active site, forming a covalent bond with Cys145 independently from reducing agents and crystallization conditions. Docking of MG-132 into Cathepsin-L well-matches with a covalent binding to the catalytic cysteine. Accordingly, MG-132 inhibits Cathepsin-L with nanomolar potency and reversibly inhibits Mpro with micromolar potency, but with a prolonged residency time. We compared the apo and MG-132-inhibited structures of Mpro solved in different space groups and we identified a new apo structure that features several similarities with the inhibited ones, offering interesting perspectives for future drug design and in silico efforts.


Subject(s)
COVID-19 Drug Treatment , Cathepsin L/drug effects , Coronavirus 3C Proteases/drug effects , Leupeptins/chemistry , Leupeptins/pharmacology , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Catalytic Domain/drug effects , Cathepsin L/chemistry , Coronavirus 3C Proteases/chemistry , Drug Design , Drug Discovery , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptidomimetics , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Virus Replication/drug effects , X-Ray Diffraction
14.
Retrovirology ; 18(1): 34, 2021 10 29.
Article in English | MEDLINE | ID: covidwho-1486582

ABSTRACT

Zhang et al. (Proc Natl Acad Sci 118:e2105968118, 2021) recently reported that SARS-CoV-2 RNA can be retrotranscribed and integrated into the DNA of human cells by the L1 retrotransposon machinery. This phenomenon could cause persistence of viral sequences in patients and may explain the prolonged PCR-positivity of SARS-CoV-2 infected patients, even long after the phase of active virus replication has ended. This commentary does critically review the available data on this topic and discusses them in the context of findings made for other exogenous viruses and ancestral endogenous retroviral elements.


Subject(s)
COVID-19 , Retroelements , Humans , RNA, Viral , SARS-CoV-2 , Virus Replication
15.
Plants (Basel) ; 10(10)2021 Oct 07.
Article in English | MEDLINE | ID: covidwho-1480919

ABSTRACT

In a search for natural compounds with anti-HIV-1 activity, we studied the effect of the ethanolic extract obtained from leaves, bark, and peels of Punica granatum L. for the inhibition of the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) and integrase (IN) LEDGF-dependent activities. The chemical analyses led to the detection of compounds belonging mainly to the phenolic and flavonoid chemical classes. Ellagic acid, flavones, and triterpenoid molecules were identified in leaves. The bark and peels were characterized by the presence of hydrolyzable tannins, such as punicalins and punicalagins, together with ellagic acid. Among the isolated compounds, the hydrolyzable tannins and ellagic acid showed a very high inhibition (IC50 values ranging from 0.12 to 1.4 µM and 0.065 to 0.09 µM of the RNase H and IN activities, respectively). Of the flavonoids, luteolin and apigenin were found to be able to inhibit RNase H and IN functions (IC50 values in the 3.7-22 µM range), whereas luteolin 7-O-glucoside showed selective activity for HIV-1 IN. In contrast, betulinic acid, ursolic acid, and oleanolic acid were selective for the HIV-1 RNase H activity. Our results strongly support the potential of non-edible P. granatum organs as a valuable source of anti-HIV-1 compounds.

16.
ACS Pharmacol Transl Sci ; 4(3): 1096-1110, 2021 Jun 11.
Article in English | MEDLINE | ID: covidwho-1313542

ABSTRACT

Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 µM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

17.
Molecules ; 26(2)2021 Jan 16.
Article in English | MEDLINE | ID: covidwho-1031148

ABSTRACT

The ongoing pandemic of severe acute respiratory syndrome (SARS), caused by the SARS-CoV-2 human coronavirus (HCoV), has brought the international scientific community before a state of emergency that needs to be addressed with intensive research for the discovery of pharmacological agents with antiviral activity. Potential antiviral natural products (NPs) have been discovered from plants of the global biodiversity, including extracts, compounds and categories of compounds with activity against several viruses of the respiratory tract such as HCoVs. However, the scarcity of natural products (NPs) and small-molecules (SMs) used as antiviral agents, especially for HCoVs, is notable. This is a review of 203 publications, which were selected using PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar, evaluates the available literature since the discovery of the first human coronavirus in the 1960s; it summarizes important aspects of structure, function, and therapeutic targeting of HCoVs as well as NPs (19 total plant extracts and 204 isolated or semi-synthesized pure compounds) with anti-HCoV activity targeting viral and non-viral proteins, while focusing on the advances on the discovery of NPs with anti-SARS-CoV-2 activity, and providing a critical perspective.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , Host-Pathogen Interactions/drug effects , SARS-CoV-2/drug effects , Severe acute respiratory syndrome-related coronavirus/drug effects , Antiviral Agents/chemistry , Biological Products/chemistry , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/physiology , Coronavirus Infections/drug therapy , Drug Evaluation, Preclinical , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Severe acute respiratory syndrome-related coronavirus/chemistry , SARS-CoV-2/chemistry , Viral Proteins/chemistry
18.
Viruses ; 12(7), 2020.
Article in English | MEDLINE | ID: covidwho-662134

ABSTRACT

HIV-1 infection requires life-long treatment and with 2.1 million new infections/year, faces the challenge of an increased rate of transmitted drug-resistant mutations. Therefore, a constant and timely effort is needed to identify new HIV-1 inhibitors active against drug-resistant variants. The ribonuclease H (RNase H) activity of HIV-1 reverse transcriptase (RT) is a very promising target, but to date, still lacks an efficient inhibitor. Here, we characterize the mode of action of N'-(2-hydroxy-benzylidene)-3,4,5-trihydroxybenzoylhydrazone (compound 13), an N-acylhydrazone derivative that inhibited viral replication (EC50 = 10 µM), while retaining full potency against the NNRTI-resistant double mutant K103N-Y181C virus. Time-of-addition and biochemical assays showed that compound 13 targeted the reverse-transcription step in cell-based assays and inhibited the RT-associated RNase H function, being >20-fold less potent against the RT polymerase activity. Docking calculations revealed that compound 13 binds within the RNase H domain in a position different from other selective RNase H inhibitors;site-directed mutagenesis studies revealed interactions with conserved amino acid within the RNase H domain, suggesting that compound 13 can be taken as starting point to generate a new series of more potent RNase H selective inhibitors active against circulating drug-resistant variants.

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