Combating Flaviviral Infections with Novel Broad-Spectrum Macrocyclic Therapeutic and Prophylactic Agents
Abstract
Although perhaps not well-known to many in the general public, emerging viral pathogens such as dengue (DENV) and Zika (ZIKV) viruses actually pose a serious and growing risk to the civilian population. One consequence of this lack of notoriety, unfortunately, is that no approved oral drugs are available against these viruses, while vaccines, even when available, have failed to provide reliable and effective solutions as was seen recently for the new dengue vaccine in the Philippines, where unexpected results were observed and the product was removed from circulation. Perhaps more critically, these diseases are transmitted by bloodsucking insects like mosquitoes and ticks, so they can spread relatively fast once established in an area. A noteworthy illustration is that just 17 months after its recent re-emergence, ZIKV was able to spread to nearly 50 countries. Further, climate change has expanded the range of such insects at the same time as environmental concerns are restricting the use of pesticides for their control. The most disturbing nature of emerging infectious diseases (a Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area) is that the danger is present, even if it may not be appreciated. Recall that the detection of ZIKV in Brazil early in 2015, and its rapid advance across the South American continent, resulted in a number of athletes choosing to forego participation in the Games of the XXXI Olympiad in Rio de Janeiro in 2016 because of the perceived risk. Although the virus was first identified almost 70 years ago, until this outbreak, the majority of infections were considered benign, including the first human epidemic in 2007 on Yap Island, Micronesia. However, ZIKV infection has now been determined to cause severe birth abnormalities in newborns (e.g., microcephaly) and is linked to neurological disorders in adults (Guillain-Barré syndrome). For U.S. military and defense personnel, who are stationed or deployed around the world, such hazards are very real since infection can affect operational readiness. As just one example, if even a single member of a Seal team cannot function at the highest level, the entire team can be placed at risk. The principal goal of the proposed project is to finally address this threat through the development of a new drug molecule that can be administered orally to quickly prevent and treat diseases caused by a large class of these infectious microorganisms, termed flaviviruses. To underscore the scope and seriousness of the global threat from these particular viruses, DENV infections are the most prevalent, with an estimated 2-4 billion people considered to be at risk, with around 390 million infections annually. West Nile virus (WNV), another family member, is now found throughout the continental United States and is already the leading cause of domestically acquired insect-borne disease in the country with a very wide incidence. As a final example, Japanese encephalitis viruses (JEV) is the main cause of viral encephalitis in many countries of Asia, causing lasting damage to the nervous system and fatality rates as high as 30%. With the continued worldwide rise in incidence and the severity of these infections, this class of viruses has become an even greater menace and novel anti-infectives, which are effective against as many of them as possible, are urgently required for treatment and protection. To achieve this goal, the applicants will use novel and innovative chemistry to optimize early-stage drug compounds previously identified in their labs. These specialized molecules have a defined shape that permits them to selectively and strongly interfere with viral reproduction through targeting and halting a vital component common among flaviviruses. The potential of these new substances as pharmaceutical agents will be assessed first in laboratory tests, then later in small animal models. The development of these as drugs will be further d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010243
Entities
People
- Helmut Thomas
Organizations
- United States Army