Meeting report: 30th International Conference on Antiviral Research, in Atlanta, GA, USA.

The 30th International Conference on Antiviral Research was held in Atlanta, GA, USA, from 21 to 25 May 2017. Each year, the International Society for Antiviral Research (ISAR) presents three major awards, this year to Mike Sofia (Elion award), David Chu (Holý award) and Maaike Everts (Prusoff award). Also this year, the inaugural ISAR Women in Science award lecture was presented by Priscilla Yang. For several years, International Conference on Antiviral Research (ICAR) has included at least one Keynote lecture, this year there were four. Although there are accounts of only these eight lectures, they reflect the diversity that is characteristic of ICAR - employment (academia, industry, public health), type of research (virus biology, potential antiviral targets, antiviral drugs, research organisation) and a range of viruses. For example, the viruses included were hepatitis C virus and hepatitis B virus (Mike Sofia), HIV and hepatitis B virus (David Chu), multiple antiviral projects (Maaike Everts), dengue (Priscilla Yang), rhinovirus C (Ann Palmenberg), polio (Mark Pallansch), HIV (Eric Hunter) and Zika virus (Pei-Yong Shi). This report ends with my personal comments giving examples in which this diversity can bring benefits. The 31st ICAR will be in Porto, Portugal, 11-15 June 2018.

Highlights of the 30th International Conference on Antiviral Research.

The 30th International Conference on Antiviral Research (ICAR) was held in Atlanta, GA, USA from May 18 to 21, 2017. This report provides an account of award lectures, invited keynote addresses and oral presentations during the meeting. The 2017 Gertrude Elion Memorial Lecture Award by Michael Sofia highlighted one of the most important accomplishments in recent drug discovery in antiviral research, the identification of the hepatitis C virus direct-acting antiviral sofosbuvir and new alternatives to combat hepatitis B virus (HBV) infection. The Antonín Holý Lecture Award by David Chu on medicinal chemistry provided an overview of early developments of nucleoside analogs for the treatment of HIV and varicella zoster virus infection and how this knowledge serves to develop new drugs targeting HBV. Priscilla Yang gave the first ISAR Women in Science lecture. She reported on pharmacological validation of new antiviral targets for dengue, Zika and other flaviviruses. The William Prusoff Young Investigator Lecture Award by Maaike Everts described the Alabama Drug Discovery Alliance and the Antiviral Drug Discovery and Development Consortium, and how they are helping to accelerate the development of new antivirals. The 30th ICAR was a success in promoting new discoveries in antiviral drug development and research. The 31st ICAR will be held in Porto, Portugal, June 11-15, 2018.

Meeting report: 29th International Conference on Antiviral Research in La Jolla, CA, USA.

The 29th International Conference on Antiviral Research (ICAR) was held in La Jolla, CA, USA from April 17 to 21, 2016. This report opens with a tribute to the late Chris McGuigan, a Past-President of ISAR, then continues with summaries of the principal invited lectures. Doug Richman (Elion Award) investigated HIV resistance, Bob Vince (Holý Award) showed how carbocyclic nucleoside analogs led to abacavir and Jerome Deval (Prusoff Award) explained how his group chose to seek a nucleoside analog to treat RSV. ALS-8176 was active in a human RSV-challenge study and is being evaluated in children. The first keynote address, by Richard H. Scheuermann, reported on the remarkable progress made in viral genomics. The second keynote address, by Heinz Feldmann, gave an overview of Ebola virus disease. There were four mini-symposia, Structural Biology, Diagnostic Technologies, DNA viruses and Zika virus. Diagnostic assays are approaching an ideal aim, a compact instrument, simple to use with any type of sample, no sample preparation and a result within an hour. The diversity of HCMV is far greater than for other herpesviruses, typically, an individual having >20,000 single nucleotide polymorphisms (SNPs). During antiviral treatment, there is rapid CMV evolution which is presumed to be due to preferential selection of already present variants rather than by the creation of new variants. A selection of contributor presentations includes oral prodrugs for nucleoside triphosphate analogs, a new method for the synthesis of phosphoramidate prodrugs and the clinical evaluation of brincidofovir for treating transplant recipients with adenovirus infections.

Meeting report: 28th International Conference on Antiviral Research in Rome, Italy.

The 28th International Conference on Antiviral Research (ICAR) was held in Rome, Italy from May 11 to 15, 2015. This article summarizes the principal invited lectures. Phillip Furman, the Elion award recipient, described the research leading to sofosbuvir. Dennis Liotta, who received the Holý award, described how an investigation into HIV entry inhibitors led to a new therapy for cancer patients. Erica Ollmann Saphire, winner of the Prusoff Young Investigator award, explored the world of viral proteins and how they remodel to perform different essential roles in viral replication. The keynote addresses, by Raffaele De Francesco and Michael Manns, reported on the remarkable progress made in the therapy of chronic HCV infections. A third keynote address, by Armand Sprecher, related the difficulties and successes of Médicins Sans Frontières in West Africa ravaged by the Ebola outbreak. There were three mini-symposia on RNA Viruses, Antiviral Chemistry and Emerging Viruses. There was a good collection of talks on RNA viruses (norovirus, rabies, dengue, HEV, HCV, and RSV). A highlight of the chemistry was the preparation of prodrugs for nucleotide triphosphates as this opens a door to new options. The third mini-symposium emphasized how research work in the antiviral area is continuing to expand and needs to do so with a sense of urgency. Although this meeting report covers only a few of the presentations, it aims to illustrate the great diversity of topics discussed at ICAR, bringing together knowledge and expertise from the whole spectrum of antiviral research.

Meeting report: 27th International conference on antiviral research, in Raleigh, NC, USA.

The 27th International Conference on Antiviral Research (ICAR) was held in Raleigh, North Carolina, USA from May 12 to 16, 2014. This article summarizes the principal invited lectures. John Drach (Elion Award) described the early days of antiviral drugs and their novel modes of action. Piet Herdewijn (Holý Award) used evolutionary pressure to select DNA polymerases that accept nucleoside analogs. Replacing thymine by 5-chlorouracil led to the generation of a new form of Escherichia coli. Adrian Ray (Prusoff Award) demonstrated how prodrugs can markedly improve both the efficacy and safety of potential drugs. The keynote addresses, by David Margolis and Myron Cohen, tackled two emerging areas of HIV research, to find an HIV "cure" and to prevent HIV transmission, respectively. These topics were discussed further in other presentations - a cure seems to be a distant prospect but there are exciting developments for reducing HIV transmission. TDF-containing vaginal rings and GSK-744, as a long-lasting injection, offer great hope. There were three mini-symposia. Although therapy with TDF/FTC gives excellent control of HBV replication, there are only a few patients who achieve a functional cure. Myrcludex, an entry inhibitor, is active against both HBV and HDV. The recent progress with HBV replication in cell cultures has transformed the search for new antiviral compounds. The HBV capsid protein has been recognized as key player in HBV DNA synthesis. Unexpectedly, compounds which enhance capsid formation, markedly reduce HBV DNA synthesis. The development of BCX4430, which is active against Marburg and Ebola viruses, is of great current interest.

Meeting report: 26th International Conference on Antiviral Research.

The 26th International Conference on Antiviral Research (ICAR) was held in San Francisco, California from May 11 to 15, 2013. This article summarizes the principal invited lectures at the meeting. The opening symposium on the legacy of the late Antonín Holý included presentations on his pioneering work with nucleotide analogs, which led to the development of several antiviral drugs including tenofovir. This drug has transformed the treatment of HIV infection and has recently become the first-line therapy for chronic hepatitis B. The Gertrude Elion Award lecturer described the anti-HIV activities of the CCR5 inhibitor cenicriviroc and the reverse transcriptase inhibitor festinavir®, and also reviewed the evaluation of biodegradable nanoparticles with adjuvant activity. The William Prusoff Award winner reported on the creation of NAOMI, a computer model with 21 enzymes to predict the activity of nucleoside analogs against hepatitis C virus (HCV). Other invited lecturers discussed the development of countermeasures against severe dengue and the potential of RNA virus capping and repair enzymes as drug targets. Topics in the clinical symposium included the current status of the anti-HCV compounds sovaprevir, ACH-3102, miravirsen and ALS-2200; the evaluation of single-tablet regimens for HIV infection; and the investigation of cytomegalovirus resistance to CMX001. Two chemistry minisymposia examined strategies and tactics in drug design and the use of in drug discovery.

Antiviral agents for herpes simplex virus.

This review starts with a brief description of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), the clinical diseases they cause, and the continuing clinical need for antiviral chemotherapy. A historical overview describes the progress from the early, rather toxic antivirals to acyclovir (ACV) which led the way for its prodrug, valacyclovir, to penciclovir and its prodrug, famciclovir (FCV). These compounds have been the mainstay of HSV therapy for two decades and have established a remarkable safety record. This review focuses on these compounds, the preclinical studies which reveal potentially important differences, the clinical trials, and the clinical experience through two decades. Some possible areas for further investigation are suggested. The focus shifts to new approaches and novel compounds, in particular, the combination of ACV with hydrocortisone, known as ME609 or zovirax duo, an HSV helicase-primase inhibitor, pritelivir (AIC316), and CMX001, the cidofovir prodrug for treating resistant HSV infection in immunocompromised patients. Letermovir has established that the human cytomegalovirus terminase enzyme is a valid target and that similar compounds could be sought for HSV. We discuss the difficulties facing the progression of new compounds. In our concluding remarks, we summarize the present situation including a discussion on the reclassification of FCV from prescription-only to pharmacist-controlled for herpes labialis in New Zealand in 2010; should this be repeated more widely? We conclude that HSV research is emerging from a quiescent phase.

Recent developments in anti-herpesvirus drugs.

Background Herpesviruses notably establish lifelong infections, with latency and reactivation. Many of the known human herpesviruses infect large proportions of the population worldwide. Treatment or prevention of herpes infections and recurrent disease still pose a challenge in the 21st century. Sources of data Original papers and review articles, meeting abstracts, a book (Clinical Virology; DD Richman, RJ Whitley & FG Hayden eds) and company web sites. Areas of agreement For herpes simplex types 1 and 2 and for varicella zoster, acyclovir (ACV; now increasingly replaced by its prodrug valacyclovir, VACV) and famciclovir (FCV) have greatly reduced the burden of disease and have established a remarkable safety record. Drug-resistance, in the otherwise healthy population, has remained below 0.5% after more that 20 years of antiviral use. In immunocompromised patients, drug resistance is more common and alternative drugs with good safety profiles are desirable. For human cytomegalovirus disease, which occurs in immunocompromised patients, ganciclovir and increasingly its prodrug valganciclovir are the drugs of choice. However, alternative drugs, with better safety, are much needed. Areas of controversy Various questions are highlighted. Should the new 1-day therapies for recurrent herpes labialis and genital herpes replace the current standard multi-day therapies? The marked differences between VACV and FCV (e.g. triphosphate stability, effect on latency) may not yet be fully exploited? Do current antivirals reduce post-herpetic neuralgia (PHN)? For immunocompromised patients with varicella zoster virus (VZV) disease, should the first-line treatment be FCV, not ACV or VACV? Should there be more support to explore new avenues for current antivirals, for example in possibly reducing herpes latency or Alzheimer's disease (AD)? Should primary Epstein-Barr virus (EBV) disease in adolescents be treated with antivirals? How can new compounds be progressed when the perceived market need is small but the medical need is great. FCV was reclassified from prescription-only to pharmacist-controlled for herpes labialis in New Zealand in 2010; should this be repeated more widely? This article reviews new drugs in clinical trials and highlights some of the problems hindering their progress.