DNDi and our partners are working to accelerate research to prepare for future viral pandemics. Utilizing our experience in non-profit drug development and partnerships with medical research institutions worldwide, our drug discovery teams are focused on identifying new broad-spectrum antivirals targeting several families of viruses recognized by WHO as presenting the greatest epidemic and pandemic potential in humans. Employing open science, AI, and cutting-edge research tools, our goal is to advance new drug candidates through Phase I safety trials to have them ready for testing against emerging viruses with pandemic potential.
Our progress in 2023 includes:
Discovery
Nucleoside Booster: A total of 128 nucleosides were physically secured for the project and six laboratories via the Helmholtz Centre for Infection Research. The compounds were sourced through collaboration with the Calibr-Skaggs Institute for Innovative Medicines and from vendors. A first report of the primary screening data for 116 compounds was received in September 2023. Four nucleosides with broad-spectrum antiviral activity and 19 nucleosides with restricted antiviral activity were identified in the report and physically resupplied to partner laboratories for further testing in December 2023.
TMEM16 series: Salicylamides such as niclosamide and nitazoxanide exhibit potent antiviral activity for a broad range of different viruses, including SARS-CoV-2, dengue, and influenza viruses. The antiviral mechanism of action is not yet fully understood, although it is suggested that they act through host mechanisms by blocking key steps in viral uptake and excretion. Furthermore, it is reported that the antiviral activity is dependent on the interaction with the TMEM16F Ca2+ ion-channel/scramblase. Significant progress in 2023 included the identification of novel analogues showing improved microsomal clearance and the development of an improved understanding of antiviral structure relationships.
AViDD ASAP: The project continued work focused on the development of novel antiviral drugs targeting three viral families: flaviviruses, coronaviruses, and enteroviruses, including two programmes on coronaviruses progressing in lead optimization. The leading programme targeting MERS/SARS-CoV-2 MPro inhibitors is expected to select a shortlist of compounds that will progress to pre-clinical studies in early 2024. The second programme, focused on SARS-CoV-2 nsp3-Mac1 inhibitors, is undergoing further validation enabled by tool compounds developed by the project. Two additional programmes are in early-stage lead optimization, with the first targeting the enterovirus EV-D68 and EV-A71 3C proteases and the second targeting the dengue and Zika virus flavivirus NS2B/3 protease.
Translation
COVID Moonshot: The COVID Moonshot project lead compound DNDI-6510 demonstrates in vivo efficacy in pre-clinical SARS-CoV-2 infection models and continues to show an excellent safety profile based on its in vitro selectivity profile and interim in vivo safety pharmacology results. Scale-up chemistry now allows for the synthesis of enantiomerically pure final product on a +100 g scale and with kilo-scale GMP manufacturing ongoing to allow for comprehensive evaluation of DNDI-6510 in non-GLP and GLP safety models, with evaluation in non-GLP safety models now ongoing.
COVID-Moonshot researchers published an article in Science Magazine, in which they explained how crowdsourcing at a massive scale and open science were key in identifying new COVID-19 antivirals designed to be accessible and affordable.
Development
ANTICOV: Following a decision to place recruitment on hold in 2022, the study was formally stopped and coordination of future consortium activities was transitioned to the Pandemic Preparedness Platform for Health and Emerging Infections Response (PANTHER).
A total of 1,941 patients were randomized in 12 countries prior to the study’s conclusion. Data cleaning and database lock were completed, and data will be transferred to the Infectious Diseases Data Observatory (IDDO) platform to ensure worldwide accessibility to other researchers.
Recruitment for ANTICOV’s ancillary studies concluded in the fourth quarter of 2022, with 512 and 434 patients recruited in the immunological and epidemiological studies, respectively. The database for the immunological study was locked on 23 December 2022. The database for the epidemiological study database was locked on 25 May 2023. Results for both studies are expected to be published in the last quarter of 2024.
Photo credit: Maneesh Agnihotri-DNDi
