RESUMO
In the development of covalent inhibitors, acrylamides warhead is one of the most popular classes of covalent warheads. In recent years, researchers have made different structural modifications to acrylamides warheads, resulting in the creation of fluorinated acrylamide warheads and cyano acrylamide warheads. These new warheads exhibit superior selectivity, intracellular accumulation, and pharmacokinetic properties. Additionally, although ketoamide warheads have been applied in the design of covalent inhibitors for viral proteins, it has not received sufficient attention. Combined with the studies in kinase inhibitors and antiviral drugs, this review presents the structural features and the progression of acrylamides warheads, offering a perspective on future research and development in this field.
Assuntos
Acrilamidas , Desenho de Fármacos , Inibidores de Proteínas Quinases , Humanos , Acrilamidas/química , Acrilamidas/síntese química , Acrilamidas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Antivirais/química , Antivirais/farmacologia , Antivirais/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A large scale of pandemic coronavirus disease (COVID-19) in the past five years motivates a great deal of endeavors donating to the exploration on therapeutic drugs against COVID-19 as well as other diseases caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein is an overview on the organic small molecules that are potentially employed to treat COVID-19 and other SARS-CoV-2-related diseases. These organic small molecules are accessed from both natural resources and synthetic strategies. Notably, typical natural products presented herein consist of polyphenols, lignans, alkaloids, terpenoids, and peptides, which exert an advantage for the further discovery of novel anti-COVID-19 drugs from plant herbs. On the other hand, synthetic prodrugs are composed of a series of inhibitors towards RNA-dependent RNA polymerase (RdRp), main protease (Mpro), 3-chymotrypsin-like cysteine protease (3CLpro), spike protein, papain-like protease (PLpro) of the SARS-CoV-2 as well as the angiotensin-converting enzyme 2 (ACE2) in the host cells. Synthetic strategies are worth taken into consideration because they are beneficial for designing novel anti-COVID-19 drugs in the coming investigations. Although examples collected herein are just a drop in the bucket, developments of organic small molecules against coronavirus infections are believed to pave a promising way for the discovery of multi-targeted therapeutic drugs against not only COVID-19 but also other virus-mediated diseases.
Assuntos
Antivirais , Produtos Biológicos , Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/síntese química , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Antivirais/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/síntese química , Pró-Fármacos/uso terapêuticoRESUMO
Cytidine has a broad range of applications in the pharmaceutical field as an intermediate of antitumor or antiviral agent. Here, a series of new cytidine peptide compounds were synthesized using cytidine and Boc group-protected amino acids and analyzed for their antiviral activities against tobacco mosaic virus (TMV). Among these compounds, the structure of an effective antiviral cytidine peptide SN11 was characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometer. The compound SN11 has a molecular formula of C15H22N6O8 and is named 2-amino-N-(2- ((1- (3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl) -2-oxo-1,2-dihydropyrimidin-4-yl) amino) -2-oxyethyl) amino). The protection, inactivation, and curation activities of SN11 at a concentration of 500 µg/mL against TMV in Nicotiana glutinosa were 82.6%, 84.2%, and 72.8%, respectively. SN11 also effectively suppressed the systemic transportation of a recombinant TMV carrying GFP reporter gene (p35S-30B:GFP) in Nicotiana benthamiana by reducing viral accumulation to 71.3% in the upper uninoculated leaves and inhibited the systemic infection of TMV in Nicotiana tabacum plants. Furthermore, the results of RNA-seq showed that compound SN11 induced differential expression of genes involved in the biogenesis and function of ribosome, plant hormone signal transduction, plant pathogen interaction, and chromatin. These results validate the antiviral mechanisms of the cytidine peptide compound and provide a theoretical basis for their potential application in the management of plant virus diseases.
Assuntos
Antivirais , Citidina , Nicotiana , Peptídeos , Doenças das Plantas , Vírus do Mosaico do Tabaco , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Citidina/farmacologia , Citidina/análogos & derivados , Citidina/química , Nicotiana/virologia , Nicotiana/química , Nicotiana/genética , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/síntese química , Doenças das Plantas/virologiaRESUMO
COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CLpro), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CLpro. Meanwhile, novel 3CLpro inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CLpro. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC50 = 97 nM) and SARS-CoV-2 replicon (EC50 = 45 nM) and low cytotoxicity (CC50 > 10 µM) in Huh7 cells. Taken together, this study devised two series of 3CLpro inhibitors and provided the potent SARS-CoV-2 3CLpro inhibitor (12b) which may be used for treating coronavirus infections.
Assuntos
Acrilatos , Antivirais , Proteases 3C de Coronavírus , SARS-CoV-2 , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , SARS-CoV-2/efeitos dos fármacos , Humanos , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Acrilatos/farmacologia , Acrilatos/química , Acrilatos/síntese química , Relação Estrutura-Atividade , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Descoberta de Drogas , COVID-19/virologia , Estrutura MolecularRESUMO
Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic ß-aminomethyl vinyl sulfone RA-0002034 (1a) is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of 1a that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of Chikungunya (CHIKV) nsP2 protease and viral replication. The vinyl sulfone covalent warhead was highly sensitive to modifications. However, alterations to the core five-membered heterocycle and aryl substituent were well tolerated. The 5-(2,5-dimethoxyphenyl)pyrazole (1o) and 4-cyanopyrazole (8d) analogs exhibited kinact/Ki ratios >9000 M-1 s-1. 3-Arylisoxazole (10) was identified as an isosteric replacement for the five-membered heterocycle, which circumvented the intramolecular cyclization of pyrazole-based inhibitors like 1a. A ligand-based model of the enzyme active site was developed to aid the design of nsP2 protease inhibitors as potential therapeutics against alphaviruses.
Assuntos
Antivirais , Vírus Chikungunya , Cisteína Endopeptidases , Sulfonas , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Relação Estrutura-Atividade , Sulfonas/farmacologia , Sulfonas/química , Sulfonas/síntese química , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/enzimologia , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Humanos , Animais , Replicação Viral/efeitos dos fármacosRESUMO
The endemic nature of the Ebola virus disease in Africa underscores the need for prophylactic and therapeutic drugs that are affordable and easy to administer. Through a phenotypic screening employing viral pseudotypes and our in-house chemical library, we identified a promising hit featuring a thiophene scaffold, exhibiting antiviral activity in the micromolar range. Following up on this thiophene hit, a new series of compounds that retain the five-membered heterocyclic scaffold while modifying several substituents was synthesized. Initial screening using a pseudotype viral system and validation assays employing authentic Ebola virus demonstrated the potential of this new chemical class as viral entry inhibitors. Subsequent investigations elucidated the mechanism of action through site-directed mutagenesis. Furthermore, we conducted studies to assess the pharmacokinetic profile of selected compounds to confirm its pharmacological and therapeutic potential.
Assuntos
Antivirais , Barreira Hematoencefálica , Ebolavirus , Tiofenos , Internalização do Vírus , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/farmacologia , Tiofenos/síntese química , Ebolavirus/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/farmacocinética , Antivirais/síntese química , Internalização do Vírus/efeitos dos fármacos , Relação Estrutura-Atividade , Animais , Descoberta de Drogas , Administração Oral , Disponibilidade Biológica , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/virologiaRESUMO
Norbelladine derivatives have garnered attention in recent years due to their diverse biological activities and pivotal role in the biosynthetic pathway of Amaryllidaceae alkaloids. This study reports the synthesis and biological evaluation of four O,N-methylated derivatives of norbelladine. These derivatives were synthesized through a three-step process: forming imine intermediates from benzaldehydes with tyramine, hydrogenating them to secondary amines, and N-methylating these amines. The products were purified and characterized by 1H and 13C NMR spectroscopy. Their biological activities were assessed by evaluating their ability to inhibit Alzheimer's disease-related enzymes acetylcholinesterase and butyrylcholinesterase. Additionally, the cytotoxic activity of the novel derivatives was tested against cancer cell lines derived from hepatocarcinoma (Huh7), adenocarcinoma (HCT-8), and acute myeloid leukemia (THP-1) cells, and their antiviral properties against a human coronavirus (HCoV-OC43), a flavivirus (dengue virus), and a lentivirus (pseudotyped HIV-1). Docking analysis was performed to understand the impact of the N-methylation on their pharmacological relevance. The results indicate that while N-methylation does not significantly affect antiviral activity, it enhances butyrylcholinesterase inhibition for N-methylnorbelladine and 4'-O,N-dimethylnorbelladine. Overall, this work enhances our understanding of norbelladine derivatives, provides new tools for Alzheimer's disease research, and lays the groundwork for future pharmaceutical developments.
Assuntos
Antivirais , Butirilcolinesterase , Simulação de Acoplamento Molecular , Humanos , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Acetilcolinesterase/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Metilação , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
seco-pregnane C21 steroids exhibit high antiviral activity against the tobacco mosaic virus (TMV). However, the structural modification of seco-pregnane C21 steroids and the structure-activity relationship (SAR) of the modified compounds remain unevaluated. Hence, the present study investigated how variations in the original skeletons of natural seco-pregnane C21 steroids affect their antiviral activity. A series of glaucogenin C and A derivatives were designed and synthesized for the first time, and their anti-TMV activity was evaluated. Bioassay results showed that most of the newly designed derivatives exhibited good to excellent antiviral activity; among these derivatives, 5g, 5j, and 5l with higher antiviral activity than that of ningnanmycin emerged as new antiviral candidates. Reverse transcription-polymerase chain reaction and Western blotting assay revealed reduced levels of TMV coat protein (TMV-CP) gene transcription and TMV-CP protein expression, which confirmed the antiviral activity of these derivatives. These compounds also downregulated the expression of NtHsp70-1 and NtHsp70-061. Computational simulations indicated that 5l displayed strong van der Waals energy and electrostatic with the TMV coat protein, affording a lower binding energy (ΔGbind = -56.2 kcal/mol) compared with Ribavirin (ΔGbind = -47.6 kcal/mol). The SAR of these compounds was also evaluated, which demonstrated for the first time that substitutions at C-3 and double bonds of C-5/C-6 and C-13/C-18 are crucial for maintaining high anti-TMV activity.
Assuntos
Antivirais , Desenho de Fármacos , Pregnanos , Vírus do Mosaico do Tabaco , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Relação Estrutura-Atividade , Pregnanos/química , Pregnanos/farmacologia , Pregnanos/síntese química , Estrutura Molecular , Doenças das Plantas/virologia , Esteroides/química , Esteroides/farmacologia , Esteroides/síntese química , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Simulação de Acoplamento MolecularRESUMO
Chikungunya virus (CHIKV) is responsible for the most endemic alphavirus infections called Chikungunya. The endemicity of Chikungunya has increased over the past two decades, and it is a pathogen with pandemic potential. There is currently no approved direct-acting antiviral to treat the disease. As part of our antiviral drug discovery program focused on alphaviruses and the non-structural protein 2 protease, we discovered that J12 and J13 can inhibit CHIKV nsP2 protease and block the replication of CHIKV in cell cultures. Both compounds are metabolically stable to human liver microsomal and S9 enzymes. J13 has excellent oral bioavailability in pharmacokinetics studies in mice and ameliorated Chikungunya symptoms in preliminary efficacy studies in mice. J13 exhibited an excellent safety profile in in vitro safety pharmacology and off-target screening assays, making J13 and its analogs good candidates for drug development against Chikungunya.
Assuntos
Antivirais , Febre de Chikungunya , Vírus Chikungunya , Modelos Animais de Doenças , Animais , Vírus Chikungunya/efeitos dos fármacos , Camundongos , Febre de Chikungunya/tratamento farmacológico , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Estrutura Molecular , Cisteína Endopeptidases/metabolismo , Microssomos Hepáticos/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Inhibition of Hepatitis B Virus (HBV) replication by small molecules that modulate capsid assembly and the encapsidation of pgRNA and viral polymerase by HBV core protein is a clinically validated approach toward the development of new antivirals. Through definition of a minimal pharmacophore, a series of isoquinolinone-based capsid assembly modulators (CAMs) was identified. Structural biology analysis revealed that lead molecules possess a unique binding mode, exploiting electrostatic interactions with accessible phenylalanine and tyrosine residues. Key analogs demonstrated excellent primary potency, absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic properties, and efficacy in a mouse model of HBV. The optimized lead also displayed potent inhibition of capsid uncoating in HBV-infected HepG2 cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP) receptor, affecting the generation of HBsAg and cccDNA establishment. Based on these results, isoquinolinone derivative AB-836 was advanced into clinical development. In Phase 1b trials, AB-836 demonstrated >3 log10 reduction in serum HBV DNA, however, further development was discontinued due to the observation of incidental alanine aminotransferase (ALT) elevations.
Assuntos
Antivirais , Desenho de Fármacos , Vírus da Hepatite B , Humanos , Relação Estrutura-Atividade , Vírus da Hepatite B/efeitos dos fármacos , Animais , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacocinética , Camundongos , Células Hep G2 , Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/antagonistas & inibidores , Isoquinolinas/farmacologia , Isoquinolinas/química , Isoquinolinas/síntese química , Quinolonas/farmacologia , Quinolonas/síntese química , Quinolonas/química , Montagem de Vírus/efeitos dos fármacosRESUMO
Nucleosides with a substituent at the 4'-position have received much attention as antiviral drugs and as raw materials for oligonucleotide therapeutics. 4'-Modified nucleosides are generally synthesized using ionic reactions through the introduction of electrophilic or nucleophilic substituents at the 4'-position. However, their synthetic methods have some drawbacks; e.g., (i) it is difficult to control stereoselectivity at the 4'-position; (ii) complex protection-deprotection processes are required; (iii) the range of electrophiles and nucleophiles is limited. With this background, we considered that a carbon radical generated at the 4'-position would be a useful intermediate for the synthesis of 4'-modified nucleosides. In this review, two novel methods for the generation of 4'-carbon radicals are summarized. The first utilizes radical deformylation involving ß-fragmentation of a hydroxymethyl group at the 4'-position. The other utilizes radical decarboxylation and 1,5-hydrogen atom transfer (1,5-HAT), which enables the generation of 4'-carbon radicals while retaining the hydroxymethyl group at the 4'-position. These methods enable the rapid and facile generation of 4'-carbon radicals and provide various 4'-modified nucleosides including 2',4'-bridged structures.
Assuntos
Antivirais , Carbono , Nucleosídeos , Nucleosídeos/síntese química , Nucleosídeos/química , Carbono/química , Radicais Livres/química , Radicais Livres/síntese química , Antivirais/síntese química , Antivirais/química , Técnicas de Química Sintética/métodos , Hidrogênio/químicaRESUMO
Dengue is an important arboviral infection worldwide for which presently there is no specific medicine. Evidence suggests there are four serotypes of dengue virus (DENV1-4), of which DENV 2 is considered to cause the most sever dengue. Therefore, this study was aimed to develop the new uridine derivatives (NUDs) against dengue virus (DENV 2). In current study 2-(3,4-dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-4-((substituted cyclohexa-2,5-dienylidene)methyl)-1,2,4-triazine-3,5(2H,4H)-dione (2a-f), were obtained via reaction of substituted uridine (1) and different aromatic aldehydes separately. Synthesized NUDs were further characterized using FTIR, 1H & 13C-NMR, mass and element analysis data. Characterized NUDs were assessed for their inhibition potential against DENV 2. Synthesized NUDs were also evaluated for their cytotoxicity towards Vero cells by MTT assay method. This investigation successfully synthesized NUDs 2a-f and reported their high inhibitory activity against DENV 2. The synthesized NUDs exhibited negligible cytotoxicity. High anti-viral activity against DENV 2 serotype and least/no cytotoxicity of NUDs suggests their importance in the treatment of dengue. Present study recommends that in future these NUDs must be investigated for their clinical importance to establish them as a choice for dengue treatment.
Assuntos
Antivirais , Vírus da Dengue , Uridina , Vírus da Dengue/efeitos dos fármacos , Uridina/análogos & derivados , Uridina/farmacologia , Uridina/síntese química , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Células Vero , Chlorocebus aethiops , Animais , Dengue/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
In this study, proximal fleximer nucleos(t)ide analogues of Bemnifosbuvir were synthesized and evaluated for their potential to serve as antiviral therapeutics. The final parent flex-nucleoside and ProTide modified flex-nucleoside analogues were tested against several viral families including flaviviruses, filoviruses, and coronaviruses. Modest activity against Zaire Ebola virus was observed at 30 µM for compound ProTide modified analogue. Neither compound exhibited activity for any of the other viruses tested. The parent flex-nucleoside analogue was screened for toxicity in CD-1 mice and showed no adverse effects up to 300 mg/kg, the maximum concentration tested.
Assuntos
Antivirais , Antivirais/síntese química , Antivirais/farmacologia , Antivirais/química , Antivirais/farmacocinética , Animais , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Humanos , Nucleosídeos de Purina/síntese química , Nucleosídeos de Purina/farmacologia , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacocinéticaRESUMO
In present study, seventeen α-nitrile substituted guaiazulene-based chalcone derivatives including twelve new were designed, synthesized, and assayed for antiviral, cytotoxicity and signal pathway activities. All derivatives showed potential antiviral activity towards influenza virus or herpes simplex virus (HSV), 7 g with the substitution of nitro group showed strong effects towards H1N1 virus at 30 µM with inhibitory rate of 66.0%, 7o with thiophene exhibited potent anti HSV-1 activities with inhibitory rate of 65.8%. Moreover, several compounds exhibited inhibitory effects on tumor cells and hypoxia-inducible factor-1 (HIF1) signaling pathways. These results showed that α-nitrile substituted guaiazulene-based chalcones offered a promising framework for the further development of new highly efficient drugs.
Assuntos
Antivirais , Azulenos , Chalconas , Azulenos/farmacologia , Azulenos/química , Azulenos/síntese química , Humanos , Estrutura Molecular , Antivirais/farmacologia , Antivirais/síntese química , Chalconas/farmacologia , Chalconas/síntese química , Linhagem Celular Tumoral , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos de Guaiano/síntese química , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Chalcona/farmacologia , Chalcona/química , Chalcona/análogos & derivados , Chalcona/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Herpesvirus Humano 1/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Desenho de Fármacos , AnimaisRESUMO
Coronaviruses are highly transmissible respiratory viruses that cause symptoms ranging from mild congestion to severe respiratory distress. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for new antivirals with broad-acting mechanisms to combat increasing emergence of new variants. Currently, there are only a few antivirals approved for treatment of SARS-CoV-2. Previously, the rocaglate natural product silvestrol and synthetic rocaglates such as CR-1-31b were shown to have antiviral effects by inhibiting eukaryotic translation initiation factor 4A1 (eIF4A) function and virus protein synthesis. In this study, we evaluated amidino-rocaglates (ADRs), a class of synthetic rocaglates with the most potent eIF4A-inhibitory activity to-date, for inhibition of SARS-CoV-2 infection. This class of compounds showed low nanomolar potency against multiple SARS-CoV-2 variants and in multiple cell types, including human lung-derived cells, with strong inhibition of virus over host protein synthesis and low cytotoxicity. The most potent ADRs were also shown to be active against two highly pathogenic and distantly related coronaviruses, SARS-CoV and MERS-CoV. Mechanistically, cells with mutations of eIF4A1, which are known to reduce rocaglate interaction displayed reduced ADR-associated loss of cellular function, consistent with targeting of protein synthesis. Overall, ADRs and derivatives may offer new potential treatments for SARS-CoV-2 with the goal of developing a broad-acting anti-coronavirus agent.
Assuntos
Antivirais , Biossíntese de Proteínas , SARS-CoV-2 , Replicação Viral , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Humanos , Chlorocebus aethiops , Animais , Biossíntese de Proteínas/efeitos dos fármacos , Células Vero , Tratamento Farmacológico da COVID-19 , Benzofuranos/farmacologia , Benzofuranos/síntese química , Benzofuranos/química , COVID-19/virologia , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Proteínas Virais/genética , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4A em Eucariotos/metabolismoRESUMO
The prevalent human pathogen, mumps virus (MuV; orthorubulavirus parotitidis) causes various complications and serious sequelae, such as meningitis, encephalitis, deafness, and impaired fertility. Direct-acting antivirals (DAAs) targeting MuV which can prevent mumps and mumps-associated complications and sequelae are yet to be developed. Paramyxoviridae family members, such as MuV, possess viral surface hemagglutinin-neuraminidase (HN) protein with sialidase activity which facilitates efficient viral replication. Therefore, to develop DAAs targeting MuV we synthesized MuV sialidase inhibitors. It is proposed that the viral HN has a single functional site for N-acetylneuraminic acid (Neu5Ac) binding and sialidase activity. Further, the known MuV sialidase inhibitor is an analog of Neu5Ac-2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA)-which lacks potency. DANA derivatives with higher MuV sialidase inhibitory potency are lacking. The MuV-HN-Neu5Ac binding site has a hydrophobic cavity adjacent to the C4 position of Neu5Ac. Exploiting this, here, we synthesized DANA derivatives with increasing hydrophobicity at its C4 position and created 3 novel sialidase inhibitors (Compounds 1, 2, and 3) with higher specificity for MuV-HN than DANA; they inhibited MuV replication step to greater extent than DANA. Furthermore, they also inhibited hemagglutination and the MuV infection step. The insight-that these 3 novel DANA derivatives possess linear hydrocarbon groups at the C4-hydroxyl group of DANA-could help develop highly potent sialidase inhibitors with high specificity for MuV sialidase, which may function as direct-acting MuV-specific antivirals.
Assuntos
Antivirais , Vírus da Caxumba , Neuraminidase , Replicação Viral , Vírus da Caxumba/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Animais , Chlorocebus aethiops , Proteína HN/metabolismo , Proteína HN/química , Células Vero , Caxumba/tratamento farmacológico , Caxumba/virologiaRESUMO
C4'-modified nucleoside analogues continue to attract global attention for their use in antiviral drug development and oligonucleotide-based therapeutics. However, current approaches to C4'-modified nucleoside analogues still involve lengthy (9-16 steps), non-modular routes that are unamenable to library synthesis. Towards addressing the challenges associated with their syntheses, we report a modular 5-step process to a diverse collection of C4'-modified nucleoside analogues through a sequence of intramolecular trans-acetalizations of readily assembled polyhydroxylated frameworks. Overall, the 2-3 fold reduction in step-count compares favorably to even recently reported biocatalytic approaches and should ultimately enable new opportunities in drug design around this popular chemotype.
Assuntos
Nucleosídeos , Nucleosídeos/química , Nucleosídeos/síntese química , Estereoisomerismo , Antivirais/síntese química , Antivirais/química , Acetais/química , Desenho de FármacosRESUMO
Natural products are a valuable resource for the discovery of novel crop protection agents. A series of γ-butyrolactone derivatives, derived from the simplification of podophyllotoxin's structure, were synthesized and assessed for their efficacy against tobacco mosaic virus (TMV). Several derivatives exhibited notable antiviral properties, with compound 3g demonstrating the most potent in vivo anti-TMV activity. At 500 µg/mL, compound 3g achieved an inactivation effect of 87.8%, a protective effect of 71.7%, and a curative effect of 67.7%, surpassing the effectiveness of the commercial plant virucides ningnanmycin and ribavirin. Notably, the syn-diastereomer (syn-3g) exhibited superior antiviral activity compared to the anti-diastereomer (anti-3g). Mechanistic studies revealed that syn-3g could bind to the TMV coat protein and interfere with the self-assembly process of TMV particles. These findings indicate that compound 3g, with its simple chemical structure, could be a potential candidate for the development of novel antiviral agents for crop protection.
Assuntos
4-Butirolactona , Antivirais , Podofilotoxina , Vírus do Mosaico do Tabaco , Podofilotoxina/química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Montagem de Vírus/efeitos dos fármacos , Proteínas do Capsídeo/metabolismo , Proteção de Cultivos , Cristalografia por Raios X , Relação Estrutura-Atividade , Nicotiana/efeitos dos fármacos , Nicotiana/metabolismo , Nicotiana/virologia , Simulação de Acoplamento MolecularRESUMO
Sporadically and periodically, influenza outbreaks threaten global health and the economy. Antigen drift-induced influenza virus mutations hamper antiviral drug development. Thus, a novel antiviral agent is urgently needed to address medication inefficacy issues. Herein, sixteen new quinoline-triazole hybrids 6a-h and 9a-h were prepared and evaluated in vitro against the H1N1 virus. In particular, 6d, 6e, and 9b showed promising H1N1 antiviral activity with selective index (SI) CC50/IC50 values of 15.8, 37, and 29.15. After that, the inhibition rates for various mechanisms of action (virus replication, adsorption, and virucidal activity) were investigated for the most efficient candidates 6d, 6e, and 9b. Additionally, their ability to inhibit neuraminidase was evaluated. With an IC50 value of 0.30 µM, hybrid 6d demonstrated effective and comparable inhibitory activity to Oseltamivir. Ultimately, molecular modeling investigations, encompassing molecular docking and molecular dynamic simulations, were conducted to provide a scientific basis for the observed antiviral results.
Assuntos
Antivirais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos , Vírus da Influenza A Subtipo H1N1 , Neuraminidase , Quinolinas , Triazóis , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/enzimologia , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Humanos , Testes de Sensibilidade Microbiana , Descoberta de Drogas , Simulação de Acoplamento MolecularRESUMO
The SARS-CoV-2 papain-like protease (PLpro), essential for viral processing and immune response disruption, is a promising target for treating acute infection of SARS-CoV-2. To date, there have been no reports of PLpro inhibitors with both submicromolar potency and animal model efficacy. To address the challenge of PLpro's featureless active site, a noncovalent inhibitor library with over 50 new analogs was developed, targeting the PLpro active site by modulating the BL2-loop and engaging the BL2-groove. Notably, compounds 42 and 10 exhibited strong antiviral effects and were further analyzed pharmacokinetically. 10, in particular, showed a significant lung accumulation, up to 12.9-fold greater than plasma exposure, and was effective in a mouse model of SARS-CoV-2 infection, as well as against several SARS-CoV-2 variants. These findings highlight the potential of 10 as an in vivo chemical probe for studying PLpro inhibition in SARS-CoV-2 infection.