This contribution will focus on the recently published article on “Nucleoside Derivatives of 2,6-Diaminopurine Antivirals: Base-Modified Nucleosides with Broad-Spectrum Antimicrobial Properties” by Maria Grazia Martina et al. focusing on the synthesis and biological evaluation of novel base-modified nucleosides and their potential use in virus-bacteria co-infections.

There is an urgent need for novel broad-spectrum antiviral agents, exemplified in the last decade, to treat newly-emerging or re-emerging viruses and potential future epidemics. Accordingly, the authors explored the world of non-natural nucleosides, which still represents one of the most successful classes of antiviral agents marketed.

In this paper the group describes the development of novel base-modified nucleosides by modification of previously existing 2,6-diaminopurine antivirals to the corresponding D/L ribonucleosides, acyclic nucleosides, and prodrug derivatives. With the aim of treating complicated virus-bacteria co-infections, these compounds have been tested against different viral families and a panel of Gram-positive and Gram-negative bacteria.

Several of the newly generated compounds displayed micromolar activity against ZIKV, WNV, DENV, and SARS-CoV-2 viruses, one of these molecules exhibited improved properties thanks to the best antiviral profile. This compound was then converted to the corresponding ProTide, masking the sugar 5’-mono-phosphate as phosphoramidate (the most common approach to bypass the slow conversion of nucleoside antivirals to their biologically active triphosphate form), to attain potential insight into its possible mechanism of action; however the loss of activity suggested that conversion to the corresponding triphosphate was not effective, suggesting a different mechanism of action from the common antiviral nuclosides.

Interestingly, some of the most promising antiviral compounds of this work, also showed moderate antibacterial activity on Enterococcus faecalis and Streptococcus pyogenes, both clinically relevant bacteria. Furthermore, these compounds showed synergistic activity on common Gram-negative opportunistic pathogens, such as K. pneumoniae and A. baumannii, which nowadays represent a major public health concern.

To see more about this project, take a look to the full article here: https://doi.org/10.1002/cmdc.202300200

• Best Practices from Hits to Lead Generation
  • Dr Rob Young (Blue Burgundy, United Kingdom)

• Design and Optimization of Hits with the Challenge of Targeting two Different Targets
  • Dr Anita Wegert (Symeres, The Netherlands) 

• The Discovery of Allosteric MALT1 Inhibitor Leads
  • Dr Jean Quancard (Novartis, Switzerland) 

• Round Table Discussion: "Best Practices from Hits to Lead Generation"
  • Dr Jean Quancard (Novartis, Switzerland) 
  • Dr Andra Unzue Lopez (Merck, Germany) 
  • Dr Anita Wegert (Symeres, The Netherlands) 
  • Dr Rob Young (Blue Burgundy, United Kingdom)

More information & registration on www.medchembio.online.

The event is free and open to everyone thanks to the support of Symeres.

ICBS2023 will feature the following scientific sessions:

• Chemoproteomics
• Chemical Biology of Aging
• Proximity-inducing drugs
• Synthetic Biology for Medicinal Chemistry
• Advances in chemical and biological conjugates
• Epigenetic therapy
• Chemical Biology on CRISPR
• RNA biology
• Physiological Models in Chemical Biology
• Target 2035

Keynote Lecturers: 

• Stefan Knapp Goethe University Frankfurt, Germany
• Shaomeng Wang University of Michigan, USA
• Ingrid Wertz, Lyterian Therapeutics, USA

Early Registration & Abstract Submission ends on September 18th.

For more information visit www.chemical-biology.org or e-mail at 2023ICBS@gmail.com.

How did you get interested in Medicinal Chemistry?

I feel that I am a somewhat unusual breed of medicinal chemist as I lead a group of organic chemists who apply synthetic technologies and methodologies to enable medicinal chemistry project teams. I have been working in this field for almost two decades following a PhD in organic synthesis, automation and biocatalysis with Prof. Nick Turner at Edinburgh University. I came to Basel for a Postdoc with Prof. Andreas Pfaltz and enjoyed my time in Switzerland so much that I never left.

Where are you currently working and what is your current position?

I am a Director in our NIBR Global Discovery Chemistry group in Basel but working globally across the Novartis portfolio of medicinal chemistry projects. As a group leader – for a group called SynTech - I have the immensely satisfying role of enabling those in my team to develop and apply impactful synthetic technologies, remove bottlenecks, and develop parallel, automated and/or scalable syntheses for our often-complex drug molecules. I am energised by my sparky, curious, and creative colleagues and it is a great privilege to work alongside them.

What do you consider your greatest achievement in your scientific career?

A few years ago, I took a sabbatical in a team to set up a workflow called MicroCycle. We have built an automated and integrated platform for drug discovery, capable of parallel synthesis, micropurification and rapid multi-parameter data generation. The experience of working in automation, and with a diverse range of scientists and experts, took me in an interesting direction and I’m really excited to see where this field will go in the future.

What advice would you give to our younger audience of researchers? 

My advice to others is to always follow your interests and never be afraid to jump into something new. I have taken some unusual turns in my career – however always following my curiosity - and have never regretted it.

Which scientist do you admire the most and why?

There are so many scientists I admire; it is hard to choose just one. I strongly admire anyone who can communicate their science to non-experts in a way that demystifies and removes stigma. We need to work on bringing science to all as it will be science that helps to find solutions to global challenges such as pandemics and climate change. For this reason, I would choose Professor Dame Sarah Gilbert, who I once saw on the news having to explain her science to unforgiving news reporters whilst developing the Oxford University/AZ vaccine at lightning speed.

Which field of medicinal chemistry do you consider the most promising for the future?

The medicinal chemistry community is buzzing with talk of AI and ML drug discovery. Of course, plenty of companies jump on this topic and we need to patiently and diligently distil out the real, pragmatic, and workable applications of these new technologies. If we can use AI/ML to design synthesisable molecules – linking with tools for retrosynthesis and reaction condition planning – then we can hopefully get to answers sooner.

TWIK-related acid-sensitive potassium (TASK) channels—members of the two pore domain potassium (K2P) channel family are found in neurons, cardiomyocytes and vascular smooth muscle cells, where they are involved in the regulation of heart rate, pulmonary artery tone, sleep/wake cycles and responses to volatile anaesthetics. K2P channels regulate the resting membrane potential, providing background K⁺ currents controlled by numerous physiological stimuli, such as pH in case of TASK. As recently published, the unique inner X-gate¹ enables TASK channels to bind inhibitors with high affinity, extraordinary selectivity and extremely slow compound washout rates, which make these inhibitors attractive chemical starting points for the treatment of sleep apnea. Here we present a chain of translatability from a classical target driven drug discovery approach to represent a molecular association between a phenotypic in vivo disease model and human disease for OSA.

Initially, ultra-high throughput screening led to the identification of a novel highly potent and selective TASK-1/TASK-3 blocker class. Medicinal Chemistry efforts led to the lead structure BAY 1000493 (1) showing the required PK properties with high clearance and short half-life to avoid any systemic side effect. However, only moderate and short in vivo efficacy in the OSA pig model² was observed after nasal application. Consequently, our optimization strategy focused on improving in vivo efficacy and duration of action in the OSA-pig model. Finally, further extensive chemical optimization culminating in the identification of BAY 2586116 (2), which was in Phase II for the treatment of OSA³. The discovery of BAY 2586116 (2) and the structural activity relationship within this class will be presented. 

Register for free here.

#GDCh (MedChem Division), #NextGenMedChem.