In the challenging frontier of drug discovery, PCSK9, as a key target in cholesterol metabolism, has long been a major area of interest in cardiovascular drug R&D. Recently, a major breakthrough was achieved by a top global pharmaceutical company, with its small molecule PCSK9 inhibitor progressing successfully into Phase III clinical trials.

Viva Biotech played a pivotal role in the early discovery and optimization of this compound by leveraging its proprietary and comprehensive technology platforms, along with the integrated efforts of multidisciplinary teams spanning structural biology, fragment screening, medicinal chemistry, and biophysics. The project progressed from a hit to a lead compound within one year and advanced to the preclinical candidate (PCC) stage within three years. The resulting PCC demonstrated picomolar (pM)-level binding affinity, underscoring the unique value of Viva Biotech's integrated drug discovery platform in tackling complex targets.

We would like to share the second edition of Viva Biotech's “Integrated Drug Discovery Platform Case Studies” series.

Project Background

The project had previously explored early discovery efforts with other service providers and identified a series of fragment hits. However, progress was hindered by the lack of clear binding site information, undefined binding modes, and limited potential for potency enhancement. To overcome these technical challenges, the project team partnered with Viva Biotech, leveraging its deep expertise in structural biology and diverse technology platforms to address key hurdles in the development of small molecule inhibitors.

Advancing Structure-Based Design to Reveal Novel Allosteric Sites

Upon receiving the fragment series, Viva Biotech's team, drawing on extensive protein engineering experience, designed a biotinylated protein construct and applied SPR assays to identify promising fragments. Over 10 protein contructs were optimized to get good quality proteins for crytsallization trail, ultimately identifying three suitable candidates.

Using both apolipoprotein (apo) and co-crystallization strategies, the team screened nearly 10,000 conditions and successfully obtained high-resolution diffraction data (<3 Å), resolving the 3D structure of the protein–compound complex.

Structural analysis revealed that the compound bound to an allosteric site distinct from the active site, enabling effective inhibition through a novel allosteric mechanism. This discovery not only introduced a new inhibition strategy but also provided a clear direction for subsequent medicinal chemistry efforts.

Through systematic medicinal chemistry optimization, Viva improved the compound's binding affinity from 930 nM to 34 nM, achieving an over 25-fold enhancement. At the cellular level, the optimized compound exhibited picomolar potency and nanomolar EC50 values. Follow-up in vivo studies demonstrated strong efficacy in non-human primates, laying a robust foundation for clinical success.

If you are interested in Viva Biotech's one-stop integrated drug discovery platform, please visit https://www.vivabiotech.com or contact our expert team at info@vivabiotech.com for further discussion.