Encephalitis, Japanese

Global landscape analysis identifies strengths and gaps in R&D pipeline to inform international pandemic preparedness efforts ROME and CAMBRIDGE, Mass., Jan. 23, 2024 /PRNewswire/ -- The INTREPID Alliance, a consortium of innovative biopharmaceutical companies dedicated to accelerating the development of antiviral treatments to help protect the world ahead of future pandemics, today published the first phase of its global landscape assessment of antiviral research and development (R&D). Antivirals are a critical part of the world's collective defense against new and known viruses. This research is intended to contribute to global pandemic preparedness efforts, including delivering on the 100 Days Mission set forth by the G7. Continue Reading The INTREPID Alliance was formed to bring together the collective industry expertise of its members across drug discovery, antiviral R&D, and medicine manufacturing to help prioritize the most promising assets in the drug development pipeline, support their advancement and catalyze new partnerships to fill in the gaps. This landscape analysis provides an initial look at the antiviral compounds currently under investigation that target 12 viral families selected by INTREPID with the greatest pandemic potential. Antivirals are a critical part of the world's collective defense against new and known viruses. Post this Key Findings: Antiviral Clinical Development Landscape This initial release of the INTREPID Alliance's Antiviral Clinical Development Landscape identifies 80 clinical programs including 61 unique compounds for nine of the 12 priority viral families.1 Of the 61 compounds, 19 are approved by stringent authority or other national authority, 26 compounds are undergoing clinical phase of development from Phases 1-3. And 16 of the 61 compounds are undergoing further information gathering by INTREPID.2 Of the 26 compounds being actively developed, all but five target coronaviruses (SARS-CoV-2) and orthomyxoviruses (Influenza) with less focus on other respiratory or vector-borne viruses of concern. In addition, several of the 19 approved compounds are also being evaluated for other viral indications. Other indications that have 1-3 compounds under development or approved include Human Adenovirus (A-G), Lassa fever, Chapare hemorrhagic fever, Ebola, Dengue, Japanese encephalitis, Crimean Congo hemorrhagic fever, Hendra virus, Rhinovirus, and Polio. Viral families with no compounds currently in clinical development are Hantaviridae, Peribunyaviridae, and Togaviridae. The majority of the developers and sponsors of these clinical-stage compounds are from the biopharmaceutical industry with nearly 88 percent representing the spectrum of small biotechs to large pharmaceutical companies. Antiviral developers within academia follow at approximately 8 percent, contract research organizations at 3 percent, and government at approximately 2 percent. "One of the many lessons from the COVID-19 pandemic is that we need to be better prepared, particularly related to the development of novel antiviral therapies that can help to treat the harmful impact of viruses, ease symptoms, and shorten the length of infection," said James Anderson, Executive Director of Global Health at the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) and Chair of the INTREPID Alliance Board. "While researchers in the industry and elsewhere continue to make progress, this landscape shows that significant gaps exist. We have the opportunity to build on the legacy of collaboration coming out of the recent pandemic to prioritize innovation in the antivirals pipeline and protect the world ahead of future pandemics." Coordination Across the Global Community In support of global pandemic preparedness efforts, INTREPID leadership joined the International Pandemic Preparedness Secretariat (IPPS) today in Rome for the launch of the 100 Days Mission Therapeutics Roadmap. A cornerstone of the IPPS's plan is the development of at least two 'Phase 2 ready' therapeutic candidates against the identified viral pathogen families of greatest pandemic potential.3 INTREPID's ongoing commitment to monitor and evaluate the wide range of antiviral compounds in development through its landscape analysis will continue to provide critical data in support of this goal. "Antiviral therapeutics are a critical component in our defense against new and emerging pandemic threats," said Victor J. Dzau, M.D., Co-Chair of the 100 Days Mission Science and Technology Expert Group. "The INTREPID Alliance's analysis of the current antiviral landscape will serve as a launchpad and continue to focus the global community on areas of urgent need and priority." Adding to this initial focus on compounds in clinical development, INTREPID is currently expanding its landscape analysis to include preclinical stage compounds. As a next step, later this year, INTREPID will publish a list of promising Phase-2 ready compounds that can be quickly deployed as antiviral compounds derived from the global landscape and scientific inspection. To improve our listing, developers are invited to submit non-confidential information on their compound candidates through an online form at the INTREPID website. The full landscape report and data are also publicly available at the INTREPID website and will be updated quarterly. The INTREPID Alliance actively engages with policymakers and public health bodies to ensure that antivirals are incentivized and integrated appropriately into global and local efforts to be better prepared against future pandemics. GLOBAL DATABASE AND STUDY METHODOLOGY The INTREPID Alliance triaged a global antiviral R&D database using stringent inclusion and exclusion criteria to arrive at the Antiviral Clinical Development Landscape. The database was licensed from Airfinity, a predictive health intelligence and data analytics firm, who monitors preclinical and clinical development of antivirals against 12 viral families that pose the greatest risk of pandemic potential. As of November 16, 2023, the Airfinity database identified 687 diverse compound/indications for the 12 priority viral families of pandemic potential; 387 were preclinical and 300 were in the clinical phase of development and/or approved by a global regulatory authority. The triage, using inclusion and exclusion criteria, of the clinical phase and approved compound/indications identified 61 distinct antiviral compounds associated with 80 compound/indications, as reported above. Consistent with INTREPID's mission of advancing small molecule antiviral development, compounds excluded from our analysis were antibodies, antibiotics and other anti-infectives, cell-based therapy, HIV or HCV-specific antivirals, host targets (including immunomodulators), natural products/nutraceuticals/herbals and vaccines. The triage of clinical phase compounds included small molecules, peptides, and RNA-based compounds with known direct antiviral mechanisms of action, in vitro/in vivo activity, first-in-human (FIH) single ascending dose vs. multiple ascending dose data completed and no major safety signals observed. ABOUT THE INTREPID ALLIANCE The INTREPID Alliance has been formed to facilitate and accelerate the development of new treatments for emerging viral pandemic agents through facilitating early science and R&D, policy and advocacy, and stakeholder engagement. Led by a consortium of innovative biopharmaceutical companies and working with the public, private and not-for-profit sectors, INTREPID works to bridge key gaps and unmet needs to ensure delivery of antiviral solutions to viral pathogens with the greatest pandemic potential. INTREPID was launched in March 2023 at a high-level summit bringing together more than 100 thought leaders in virology and global health. For a read-out from the summit and additional information, visit . 1 12 priority viral families identified by the INTREPID Alliance Scientific Working Group using the NIH/NIAID priority viral family list; World Health Organization priority disease areas; and Airfinity database of antivirals. 2 INTREPID Alliance: Antiviral Clinical Development Landscape. 24 January 2024. 3 World Health Organization priority disease areas. Accessed 24 January 2024. SOURCE INTREPID Alliance

Viruses have limited genetic material -- and few proteins -- so all the pieces must work extra hard. Zika is a great example; the virus only produces 10 proteins. Now researchers have shown how the virus does so much with so little and may have identified a therapeutic vulnerability. Viruses have limited genetic material -- and few proteins -- so all the pieces must work extra hard. Zika is a great example; the virus only produces 10 proteins. Now, in a study published in the journal PLOS Pathogens, researchers at Sanford Burnham Prebys have shown how the virus does so much with so little and may have identified a therapeutic vulnerability. In the study, the research team showed that Zika's enzyme -- NS2B-NS3 -- is a multipurpose tool with two essential functions: breaking up proteins (a protease) and dividing its own double-stranded RNA into single strands (a helicase). "We found that Zika's enzyme complex changes function based on how it's shaped," says Alexey Terskikh, Ph.D., associate professor at Sanford Burnham Prebys and senior author of the paper. "When in the closed conformation, it acts as a classic protease. But then it cycles between open and super-open conformations, which allows it to grab and then release a single strand of RNA -- and these functions are essential for viral replication." Zika is an RNA virus that's part of a family of deadly pathogens called flaviviruses, which include West Nile, dengue fever, yellow fever, Japanese encephalitis and others. The virus is transmitted by mosquitoes and infects uterine and placental cells (among other cell types), making it particularly dangerous for pregnant women. Once inside host cells, the virus re-engineers them to produce more Zika. Understanding Zika on the molecular level could have an enormous payoff: a therapeutic target. It would be difficult to create safe drugs that target the domains of the enzyme needed for protease or helicase functions, as human cells have many similar molecules. However, a drug that blocks Zika's conformational changes could be effective. If the complex can't shape-shift, it can't perform its critical functions, and no new Zika particles would be produced. An efficient machine Researchers have long known that Zika's essential enzyme was composed of two units: NS2B-NS3pro and NS3hel. NS2B-NS3pro carries out protease functions, cutting long polypeptides into Zika proteins. However, NS2B-NS3pro's abilities to bind single-stranded RNA and help separate the double-stranded RNA during viral replication were only recently discovered. In this study, the researchers leaned on recent crystal structures and used protein biochemistry, fluorescence polarization and computer modeling to dissect NS2B-NS3pro's life cycle. NS3pro is connected to NS3hel (the helicase) by a short amino acid linker and becomes active when the complex is in its closed conformation, like a closed accordion. The RNA binding happens when the complex is open, whereas the complex must transition through the super-open conformation to release RNA. These conformational changes are driven by the dynamics of NS3hel activity, which extends the linker and eventually "yanks" the NS3pro to release RNA. NS3pro is anchored to the inside of the host cell's endoplasmic reticulum (ER) -- a key organelle that helps shepherd cellular proteins to their appropriate destinations -- via NS2B and, while in the closed conformation, cuts up the Zika polypeptide, helping generate all viral proteins. On the other side of the linker, NS3hel separates Zika's double-stranded RNA and conveniently hands a strand over to NS3pro, which has positively charged "forks" to grab on to the negatively charged RNA. "There's a very nice groove of positive charges," says Terskikh. "So, RNA just naturally follows that groove. Then the complex shifts to the closed conformation and releases the RNA." As NS3hel reaches forward to grab the double-stranded RNA, it pulls the complex with it; however, since the NS3pro is anchored in the ER membrane, and the linker can only extend so far, the complex snaps into the super-open conformation and releases RNA. The complex then relaxes back to the open conformation, ready for a new cycle. Meanwhile, when NS3pro detects a viral polypeptide to cut, it forces the complex into the closed conformation, becoming a protease. The authors call this process "reverse inchworm," because grabbing and releasing the single-stranded RNA resembles inchworm movements, but backward, with the jaws (the protease) trailing behind. In addition to providing a possible therapeutic target for Zika, this detailed understanding could be applied to other flaviviruses, which share similar molecular machinery. "Versions of the NS2B-NS3pro complex are found throughout the flaviviruses," says Terskikh. "It could potentially constitute a whole new class of drug targets for multiple viruses."

A simple-to-apply, needle-free vaccine patch is being developed to protect people from the potentially deadly mosquito-borne Zika virus. A simple-to-apply, needle-free vaccine patch is being developed to protect people from the potentially deadly mosquito-borne Zika virus. A prototype using The University of Queensland-developed and Vaxxas-commercialised high-density microarray patch (HD-MAP) has delivered a University of Adelaide-developed vaccine and elicited an effective immune response to Zika virus in mice. UQ alum and Vaxxas researcher Dr Danushka Wijesundara said Zika virus was a risk to people across the Pacific, Southeast Asia, India, Africa and South and Central America. "We can change the way we combat Zika virus with the HD-MAP patch because it is an effective, pain-free, simple to apply, and easy to store vaccination method," Dr Wijesundara said. "HD-MAP delivers the vaccine to immune cells beneath the skin's surface with thousands of tiny microprojections. "In our pre-clinical trial, the vaccine provided rapid protection against live Zika virus, targeting a specific protein called NS1 which is crucial to the virus's survival. "The vaccine patch evoked T-cell responses that were about 270 per cent higher than from a needle or syringe vaccine delivery." Zika virus generally causes a mild illness but infection in pregnancy can lead to miscarriage and stillbirths or infants born with congenital malformations. In February 2016, the World Health Organization declared a Public Health Emergency of International Concern when Zika virus spread across 40 countries in Latin America, causing more than 1.5 million confirmed or suspected cases in a 6-month period. The University of Adelaide's Associate Professor Branka Grubor-Bauk said limited global surveillance shows Zika virus is active in at least 89 countries and territories but there is no currently licensed vaccine. "This vaccine is unique because it targets a protein inside, rather than outside of the virus meaning it won't enhance the symptoms of closely related viruses such as dengue fever, in people who've been vaccinated," Dr Grubor-Bauk said. Dr David Muller from UQ's School of Chemistry and Molecular Biosciences said the microarray patch and the vaccine could have benefits beyond the ability to protect from Zika virus. "Because the protein we're targeting plays a central role in replication in a virus family known as flaviviruses, there's the potential to apply our approach to target other flaviviruses such as dengue or Japanese encephalitis," Dr Muller said. "It could also deliver a vaccine mixture to target the whole family of viruses, providing greater protection. "A major benefit of the HD-MAP delivery platform is vaccine stability at elevated temperatures -- we found the patch retained vaccine potency when stored at 40 degrees Celsius for up to four weeks. "This increases the reach of vaccines in low- and middle-income countries where refrigeration is challenging." The research team would like to acknowledge the National Health and Medical Research Centre (NHMRC) for funding awarded to Dr Muller and The Hospital Research Foundation Group Fellowship awarded to Dr Branka Grubor-Bauk, who supported the project.