Antiviral Chemistry & Chemotherapy publishes the results of original research concerned with the biochemistry, mode of action, chemistry, pharmacology and virology of antiviral compounds. Manuscripts dealing with molecular biology, animal models and vaccines are welcome.     The journal also publishes reviews, pointers, short communications and correspondence.

Antiviral Chemistry and Chemotherapy publishes original research results related to the biochemistry, mode of action, chemistry, pharmacology, and virology of antiviral compounds. Manuscripts addressing molecular biology, animal models, and vaccines are also welcome. The journal additionally publishes reviews, pointers, short communications, and correspondence.

《Antiviral Chemistry and Chemotherapy》期刊致力于发表与抗病毒化合物的生物化学、作用机制、化学、药理学和病毒学相关的原创研究成果。欢迎提交涉及分子生物学、动物模型和疫苗的手稿。此外，期刊还接受综述、指引、简短通讯和信函的投稿。

Antiviral Chemistry and Chemotherapy

We recently described the synthesis and antiviral activity of the compounds 5-phenyl-3-(4-cyano-5-phenylisothiazol-3-yl) disulphanyl-4-isothiazolecarbonitrile and S-(4-cyano-5-phenylisothiazol -3-yl)-O-ethyl thiocarbonate, which were found to be effective against both HIV-1 (IIIB) and HIV-2 (ROD). We have now evaluated these compounds against both RNA and DNA viruses, obtaining high selectivity indexes for poliovirus 1 (SI: 223 and 828, respectively) and Echovirus 9 (SI: 334 and 200, respectively). In our previous studies, 3-methylthio-5-(4-OBn-phenyl)-4-isothiazolecarbonitrile was found to exhibit a broad spectrum of action against picornaviruses, we therefore selected this compound and S-(4-cyano-5-phenylisothiazol-3-yl)-O-ethyl thiocarbonate as the model for the synthesis of a new isothiazole derivative, S-[4-cyano-5-(4-OBn-phenyl)isothiazol-3-yl]-O-ethyl thiocarbonate. This compound was evaluated against picornaviruses, measles virus, HIV-1 (IIIB) and HIV-2 (ROD), and some DNA viruses (adenovirus type 2 and herpes simplex virus type 1). The compound was shown to be active against rhinoviruses 2, 39, 86 and 89, Coxsackie B1 and measles virus.

Adriana Garozzo

Christian CC Cutri

Christophe Pannecouque

Angelo Castro

Francesco Guerrera

Erik De Clercq

Antiviral chemistry & chemotherapy

Isothiazole Derivatives as Antiviral Agents

异噻唑衍生物作为抗病毒剂

While noncanonic xanthine nucleotides XMP/dXMP play an important role in balancing and maintaining intracellular purine nucleotide pool as well as in potential mutagenesis, surprisingly, acyclic nucleoside phosphonates bearing a xanthine nucleobase have not been studied so far for their antiviral properties. Herein, we report the synthesis of a series of xanthine-based acyclic nucleoside phosphonates and evaluation of their activity against a wide range of DNA and RNA viruses. Two acyclic nucleoside phosphonates within the series, namely 9-[2-(phosphonomethoxy)ethyl]xanthine (PMEX) and 9-[3-hydroxy-2-(phosphonomethoxy)propyl]xanthine (HPMPX), were shown to possess activity against several human herpesviruses. The most potent compound was PMEX, a xanthine analogue of adefovir (PMEA). PMEX exhibited a single digit µM activity against VZV (EC50 = 2.6 µM, TK+ Oka strain) and HCMV (EC50 = 8.5 µM, Davis strain), while its hexadecyloxypropyl monoester derivative was active against HSV-1 and HSV-2 (EC50 values between 1.8 and 4.0 µM). In contrast to acyclovir, PMEX remained active against the TK- VZV 07-1 strain with EC50 = 4.58 µM. PMEX was suggested to act as an inhibitor of viral DNA polymerase and represents the first reported xanthine-based acyclic nucleoside phosphonate with potent antiviral properties.

Ondřej Baszczyňski

Martin Maxmilian Kaiser

Michal Česnek

Petra Břehová

Petr Jansa

Eliška Procházková

Martin Dračínský

Robert Snoeck

Graciela Andrei

Zlatko Janeba

Xanthine-based acyclic nucleoside phosphonates with potent antiviral activity against varicella-zoster virus and human cytomegalovirus

基于黄嘌呤的无环核苷膦酸化合物对水痘-带状疱疹病毒和人类巨细胞病毒具有强效抗病毒活性

Background Rilpivirine (TMC278LA) is a promising drug for pre-exposure prophylaxis of HIV-1 because of its sub-nanomolar potency and long-acting formulation; however, increasing transmission of non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 with potential cross-resistance to rilpivirine could reduce its preventive efficacy. This study investigated rilpivirine cross-resistance among recombinant subtype C HIV-1 derived from 100 individuals failing on first-line non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy in South Africa whose samples were sent for routine HIV-1 drug resistance testing to Lancet Laboratories (Johannesburg, South Africa). Methods Plasma samples were selected from individuals with HIV-1 RNA > 10,000 copies/ml and ≥1 non-nucleoside reverse transcriptase inhibitor-resistance mutation in reverse transcriptase. Recombinant HIV-1LAI-containing bulk-cloned full-length reverse transcriptase sequences from plasma were assayed for susceptibility to nevirapine (NVP), efavirenz (EFV) and rilpivirine in TZM-bl cells. Fold-change (FC) decreases in drug susceptibility were calculated against a mean IC50 from 12 subtype C HIV-1 samples from treatment-naïve individuals in South Africa. Cross-resistance was evaluated based on biological cutoffs established for rilpivirine (2.5-FC) and the effect of mutation combinations on rilpivirine phenotype. Results Of the 100 samples from individuals on failing antiretroviral therapy, 69 had 2.5- to 75-fold decreased susceptibility to rilpivirine and 11 had >75-fold resistance. Rilpivirine resistance was strongly associated with K103N especially in combination with other rilpivirine-associated mutations. Conclusion The frequently observed cross-resistance of HIV-1 suggests that the preventive efficacy of TMC278LA pre-exposure prophylaxis could be compromised by transmission of HIV-1 from individuals with failure of first-line non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy.

Kerri J Penrose

Chanson J Brumme

Maritsa Scoulos-Hanson

Kristen Hamanishi

Kelley Gordon

Raquel V Viana

Carole L Wallis

P Richard Harrigan

John W Mellors

Urvi M Parikh

Frequent cross-resistance to rilpivirine among subtype C HIV-1 from first-line antiretroviral therapy failures in South Africa

南非一线抗逆转录病毒治疗失败中C亚型HIV-1对利匹韦林的频繁交叉耐药性

Respiratory syncytial virus is the leading cause of pneumonia and bronchiolitis in infants and is a serious health risk for elderly and immunocompromised individuals. No vaccine has yet been approved to prevent respiratory syncytial virus infection and the only available treatment is immunoprophylaxis of severe respiratory syncytial virus disease in high-risk infants with Palivizumab (Synagis®). The development of respiratory syncytial virus vaccine has been hampered by the phenomenon of enhanced respiratory syncytial virus disease observed during trials of a formalin-inactivated respiratory syncytial virus in 1960s. A search for effective respiratory syncytial virus therapeutics has been complicated by the fact that some of the most advanced respiratory syncytial virus antivirals, while highly effective in a prophylactic setting, had not demonstrated clinical efficacy when given after infection. A number of respiratory syncytial virus vaccines and antivirals are currently under development, including several vaccines proposed for maternal immunization. The cotton rat Sigmodon hispidus is an animal model of respiratory syncytial virus infection with demonstrated translational value. Special cohort scenarios, such as infection under conditions of immunosuppression and maternal immunization have been modeled in the cotton rat and are summarized here. In this review, we focus on the recent use of the cotton rat model for testing respiratory syncytial virus vaccine and therapeutic candidates in preclinical setting, including the use of special cohort models. An overview of published studies spanning the period of the last three years is provided. The emphasis, where possible, is made on candidates in the latest stages of preclinical development or currently in clinical trials.

MS Boukhvalova

KC Yim

JCG Blanco

Cotton rat model for testing vaccines and antivirals against respiratory syncytial virus

用于测试呼吸道合胞病毒疫苗和抗病毒药物的棉鼠模型

Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies.

Joy Y Feng

Addressing the selectivity and toxicity of antiviral nucleosides

解决抗病毒核苷的选择性和毒性问题

Respiratory syncytial virus infections recur throughout life despite induction of immunity by the first natural infection. An effective vaccine has long been sought but no vaccine is currently licensed, although promising candidates are currently being developed based on greater knowledge of the virus properties. However, there are significant populations that may not be protected adequately by a vaccine or are unable to be vaccinated. Thus, there is a continued need for effective therapeutic agents to treat the infection, especially in higher-risk individuals, a perspective presented in this article.

Norbert J Roberts

The continuing need for therapeutic agents for respiratory syncytial virus infection

呼吸道合胞病毒感染治疗药物的持续需求

Brivudin, (( E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU) can be considered the gold standard for the treatment of varicella-zoster virus (VZV) infections, such as herpes zoster (shingles). It is available for clinical use in most European countries (except for the UK) and over the whole world (except for the US and Canada). Besides VZV its activity spectrum also includes various other herpesviruses, such as herpes simplex virus type 1 (HSV-1). Its activity against VZV and HSV-1 depends on phosphorylation by the virus-encoded thymidine kinase (TK). In its active form (BVDU TP or BVDU 5’-triphosphate), it can act as both substrate and inhibitor of the viral (i.e., HSV-1) DNA polymerase. It has proven to be effective against herpes zoster, including post-herpetic neuralgia (PHN). It is contra-indicated in patients concomitantly treated by 5-fluorouracil (FU), since its degradation product, ( E)-5-(2-bromovinyl)uracil, is inhibitory to the catabolism of FU, which may enhance the toxicity of the latter. A new compound, the bicyclic nucleoside analogue (BCNA) Cf-1743, has been described, which is a more potent inhibitor of VZV replication than BVDU and which does not interfere with the catabolism of FU. It is applicable orally, as its 5’-valine ester FV-100 (Fermavir), but has not (yet) been marketed for clinical use.

The development of BVDU: An odyssey

BVDU的发展：一段奥德赛之旅

Bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV). and bovine coronavirus (BCV) threaten the productivity of cattle worldwide. Development of therapeutics that can control the spread of these viruses is an unmet need. The present research was designed to explore the in vitro antiviral activity of the Nerium oleander derived cardiac glycoside oleandrin and a defined N. oleander plant extract (PBI-05204) containing oleandrin.Madin Darby Bovine Kidney (MDBK) cells, Bovine Turbinate (BT) cells, and Human Rectal Tumor-18 (HRT-18) cells were used as in vitro culture systems for BVDV, BRSV and BCV, respectively. Cytotoxicity was established using serial dilutions of oleandrin or PBI-05204. Noncytotoxic concentrations of each drug were used either prior to or at 12 h and 24 h following virus exposure to corresponding viruses. Infectious virus titers were determined following each treatment.Both oleandrin as well as PBI-05204 demonstrated strong antiviral activity against BVDV, BRSV, and BCV, in a dose-dependent manner, when added prior to or following infection of host cells. Determination of viral loads by PCR demonstrated a concentration dependent decline in virus replication. Importantly, the relative ability of virus produced from treated cultures to infect new host cells was reduced by as much as 10,000-fold at noncytotoxic concentrations of oleandrin or PBI-05204.The research demonstrates the potency of oleandrin and PBI-05204 to inhibit infectivity of three important enveloped bovine viruses in vitro. These data showing non-toxic concentrations of oleandrin inhibiting infectivity of three bovine viruses support further investigation of in vivo antiviral efficacy.

Robert A. Newman

Christopher C.L. Chase

Jose R. Matos

Karim Abdelsalam

Robin Buterbaugh

Sonja Van Holland

Hadia Abdelaal

Amelia Woolum

K Jagannadha Sastry

Efficacy of oleandrin and PBI-05204 against bovine viruses of importance to commercial cattle health

牛重要商业健康病毒的抗病毒活性：夹竹桃苷与PBI-05204的疗效

The water-based combination of two inorganic chemical compounds such as sodium tungstate dihydrate-Na2WO4 × 2H2O and Aluminum sulfate octadecahydrate-Al2 (SO4) 3 × 18H2O that we have conditionally named 'Vomifal' has a broad antiviral activity in various DNA and RNA viruses, including Human Herpes Virus (HHV), African Swine Fever Virus (ASFV), Vaccinia Virus (VV), Hepatitis C Virus (HCV), Foot and Mouth Disease Virus (FMDV), Influenza A virus (A/Aichi/2/68 (H3N2)). In vitro and In vivo assays in several tissue cultures as well as in laboratory animals, conformed 'Vomifal' has a very low toxicity and the antiviral properties partially are due to its ability to induce gamma-IFN. Based on the results obtained, we can assume the presence of at least two mechanisms of the antiviral action of the studied drug. First or early stage - an unknown mechanism, possibly related to the effect on cellular receptors. Second or late stage - main antiviral properties probably associated with an interferonogenic effect.

Hranush Avagyan

Anaida Mirzoyan

Ferdinand Mirzoyan

Roza Izmailyan

Sona Hakobyan

Henry Voskanyan

Zara Semerjyan

Aida Avetisyan

Hranush Arzumanyan

Elena Karalova

Liana Abroyan

Lina Hakobyan

Nane Bayramyan

Nazeli Gevorgyan

Alexander Karalyan

Zaven Karalyan

New composition of tungsten has a broad range of antiviral activity

钨的新成分具有广泛的抗病毒活性

Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA. Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate ∼10%) and require lifelong treatment for most patients. As such, antiviral agents with novel mechanisms of action are needed. Active site polymerase inhibitor nucleotides (ASPINs) noncompetitively distort the HBV polymerase active site to completely inhibit all polymerase functions, unlike traditional chain-terminating nucleos(t)ide analogues, which only target select polymerase functions and are consumed in the process. Clevudine, a first-generation ASPIN, demonstrated potent and prolonged HBV suppression in phase 2 and 3 clinical studies, but long-term treatment was associated with reversible myopathy in a small number of patients. ATI-2173, a novel next-generation ASPIN, is structurally similar to clevudine but targets the liver and demonstrates potent anti-HBV activity on and off treatment, and may ultimately demonstrate an improved pharmacokinetic and safety profile by significantly reducing systemic clevudine exposure. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection.

Robert G Gish

Tarik Asselah

Katherine Squires

Douglas Mayers

Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens

活性位点聚合酶抑制核苷酸（ASPINs）：慢性HBV治愈方案的潜在药物

ISSN	0956-3202, 2040-2066
h-index	59

涉及主题	生物遗传学医学化学生物化学病毒学免疫学病毒基因有机化学家庭医学人类免疫缺陷病毒（HIV）体外立体化学内科学病毒性疾病物理药理学细胞培养核磁共振酶核糖核酸核苷
出版信息	出版商: SAGE Publications Inc.，出版周期: ，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 2017，原创研究文献占比: 0.00%，自引率:N.A.， Gold OA占比: 0.00%
平均审稿周期	网友分享经验：15 Weeks

Antiviral Chemistry and Chemotherapy

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