Antiviral Chemistry and Chemotherapy最新文献

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.

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.

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.

As a result of the multiple gathering and travels restrictions during the SARS-CoV-2 pandemic, the annual meeting of the International Society for Antiviral Research (ISAR), the International Conference on Antiviral Research (ICAR), could not be held in person in 2021. Nonetheless, ISAR successfully organized a remote conference, retaining the most critical aspects of all ICARs, a collegiate gathering of researchers in academia, industry, government and non-governmental institutions working to develop, identify, and evaluate effective antiviral therapy for the benefit of all human beings. This article highlights the 2021 remote meeting, which presented the advances and objectives of antiviral and vaccine discovery, research, and development. The meeting resulted in a dynamic and effective exchange of ideas and information, positively impacting the prompt progress towards new and effective prophylaxis and therapeutics.

The idea to start the Rega Foundation was conceived in 1971 at an informal meeting organized by Prof. Piet De Somer (where Prof. Alfons Billiau, Prof. André Vlerick and I were also present), before the Foundation was formally created in 1972. From the early years some antiviral compounds, such as BVDU and the aminoacyl esters of acyclovir (from which ultimately valacyclovir evolved) originated. The advent of AIDS in 1981 and the discovery of the etiologic agent (HIV) thereof in 1983 have led to the identification of an avalanche of anti-HIV compounds in which the Rega Institute has played a primordial role. Foremost among these compounds was tenofovir, discovered in collaboration with Antonín Holý from the IOCB (Institute of Organic Chemistry and Biochemistry) in Prague. Tenofovir laid the basis for the treatment of HIV (AIDS) and hepatitis B virus (HBV) infections, and in combination with emtricitabine it was the first chemical ever approved by the US FDA (Food and Drug Administration) for the prophylaxis of HIV infections.

Introduction: Maraviroc inhibits CCR5-tropic HIV-1 across different subtypes in vitro and has demonstrated efficacy in clinical trials. V3-loop amino acid variants observed in individual maraviroc-resistant viruses have not been found to be predictive of reduced susceptibility. Sequence-database searches have demonstrated that approximately 7.3% of viruses naturally encode these variants, raising concerns regarding potential pre-existing resistance. A study from Russia reported that combinations of these same amino acids are present in the V3 loops of the Russian variant subtype A (IDU-A, now A6) with a much greater prevalence (range: 74.4%-92.3%) depending on the combination. However, these studies and database searches did not include phenotypic evaluation.

Methods: Sixteen Russian HIV-1 isolates (including sub-subtype A6 viruses) were assessed for V3 loop sequence and phenotypic susceptibility to maraviroc.

Results: All 12 of the A6 viruses and 2/4 subtype B isolates encoded V3-loop variants that have previously been identified in individual virus isolates with reduced susceptibility to maraviroc. However, despite the prevalence of these V3-loop amino acid variants among the tested viruses, phenotypic sensitivity to maraviroc was observed in all instances. Similarly, reduced susceptibility to maraviroc was not found in virus from participants who experienced virologic failure in a clinical study of maraviroc in Russia (A4001101, [NCT01275625]).

Discussion: Altogether, these data confirm that the presence of individual or combinations of V3-loop amino acid residues in sub-subtype A6 viruses alone does not predict natural resistance to maraviroc and that V3-loop genotype analysis of R5 virus prior to treatment is not helpful in predicting clinical outcome.

Viruses from 15 of 35 maraviroc-treated participants with virologic failure and CCR5-tropic (R5) virus in the MOTIVATE studies at Week 24 had reduced maraviroc susceptibility. On-treatment amino acid changes were observed in the viral envelope glycoprotein 120 third variable (V3)-loop stems and tips and differed between viruses. No amino acid change reliably predicted reduced susceptibility, indicating that resistance was genetic context-dependent. Through Week 24, poor adherence was associated with maraviroc-susceptible virologic failure, whereas reduced maraviroc susceptibility was associated with suboptimal background regimen activity, highlighting the importance of overall regimen activity and good adherence. Predictive values of pretreatment V3-loop sequences containing these Week 24 mutations or other variants present at >3% in pretreatment viruses of participants with virologic failure at Week 48 were retrospectively assessed. Week 48 clinical outcomes were evaluated for correlates with pretreatment V3-loop CCR5-tropic sequences from 704 participants (366 responders; 338 virologic failures [83 with R5 virus with maraviroc susceptibility assessment]). Seventy-five amino acid variants with >3% prevalence were identified among 23 V3-loop residues. Previously identified variants associated with resistance in individual isolates were represented, but none were associated reliably with virologic failure alone or in combination. Univariate analysis showed virologic-failure associations with variants 4L, 11R, and 19S (P < 0.05). However, 11R is a marker for CXCR4 tropism, whereas neither 4L nor 19S was reliably associated with reduced maraviroc susceptibility in R5 failure. These findings from a large study of V3-loop sequences confirm lack of correlation between V3-loop genotype and clinical outcome in participants treated with maraviroc.Clinical trial registration numbers (ClinicalTrials.gov): NCT00098306 and NCT00098722.