ALPX
Fast Track The Drug Discovery Journey With ALPX

In the dynamic field of drug discovery and a competitive landscape, ALPX has an outstanding track record as an innovative and efficient Contract Research Organisation (CRO) spin-off from the European Molecular Biology Laboratory (EMBL), supporting pharmaceutical and biotech companies that are bringing the future life-saving therapeutics to the market.

ALPX specializes in Structure-Based Drug Design (SBDD) and offers automated X-ray crystallography services applying the unique cutting-edge technologies CrystalDirect and CRIMS (Crystallographic Information Management System). The integrated protein-to-structure pipelines developed by ALPX cover a large spectrum of crystallographic activities for challenging targets - driven by a team of dedicated scientists who have developed expertise in crystallization screening, crystal optimization, large-scale small molecule screening, data collection, and structure refinement.

CrystalDirect and CRIMS: The Technology Powerhouse

At the heart of their automated pipelines lies the groundbreaking technology CrystalDirect. This unique approach offers a complete hardware ecosystem to modern crystallographers - enabling high throughput crystallization on CrystalDirect trays and providing an automated harvesting solution called the CrystalDirect harvester. The automated crystal mounting controlled by a harvester robot makes the tedious sample preparations streamlined, swift, and effective. Laser-induced photoablation applies across various crystal morphologies and allows for delicate crystal surgery, wherein the most optimal part of an existing crystal is delicately excised and isolated. The performance of this IP-protected technology reduces mechanical stress on the crystals while ensuring better reproducibility when compared to crystals fished manually. This precision helps get the best out of all crystal systems, especially from the most complicated morphologies, often associated with challenging targets and large complexes. The advent of CrystalDirect technology overcomes the last bottleneck for SBDD using X-ray crystallography.

Complementing CrystalDirect is CRIMS, a sophisticated online software suite that seamlessly tracks experiments, making real-time data accessible to scientists through intuitive interfaces. CRIMS empowers scientists with unparalleled access and control to their projects for monitoring the results and driving the experimental setup, fostering collaboration, and ensuring that every step is executed fast and with precision. This cooperative platform helps schedule, monitor, and report all the projects under secure accounts, allowing management and hands-on personnel to track the progression worldwide. CRIMS perfectly embodies the transparency mindset of the ALPX team. This open-door policy fosters trust and full control, ensuring that all stakeholders are aligned throughout the drug discovery journey.

The CrystalDirect-based automated pipeline was recently applied for a collaborative study performed jointly with scientists from EMBL Hamburg and Grenoble, focusing on determining the plasticity of the binding pocket in peptide transporters for promiscuous substrate recognition, for which multiple high-quality co-structures were obtained (Kotov et al., Cell Reports, 2023).

The Next Phase of Evolution in Drug Discovery

The drug development industry has undergone significant transformations in recent years, where novel processes speed up the turnover for SBDD from protein production to data processing. The technologies used by ALPX can significantly contribute to accelerating the delivery time of high-resolution structures with frequent access to top-notch beamlines feeding the medicinal chemistry iteration loop every week.

The ALPX pipeline makes X-ray crystallography accessible to all SBDD projects looking for quick structural information of targeted proteins in complex with lead compounds. The rapid turnover for each intermediate ligand is crucial to reducing the expenses and duration involved in a drug investigation and their subsequent market introduction.

With ALPX, all the sectors of protein X-ray crystallography are now extensively automated, increasing the throughput and allowing the method to be classified as a screening tool that enables a systematic and focused strategy for discovering and refining leading compounds.

“Using cutting-edge technology and dedicated expertise, our company has been reshaping the drug discovery paradigm. We're strategically focused on rapidly delivering structures to fast-track the success of our collaborators.,” says Irina Cornaciu-Hoffmann, ALPX CEO and co-founder.

The company’s results-driven approach aligns perfectly with the strategies of major pharmaceutical and biotech firms, complementing their advanced approaches.

The latest AI developments in the structural biology community can be integrated at multiple levels in the pipelines used by ALPX, helping with decision-making for the crystallization refinement, harvesting or data processing. ALPX has already witnessed the interest of the SBDD community in AI-driven predictions regarding the binding mode where experimental data is still needed for validation of the in-silico models.

“We're constantly optimizing our pipelines, through internal R&D and continuous development and growth. We have a flexible approach, tailored to meet the clients’ demands and we are currently expanding in the areas of membrane proteins and biologics,” says Damien Clavel, ALPX senior technical officer.

A Glimpse into the Novel Approach

ALPX's current process stands out for its commitment to transparency and efficiency. Unlike traditional black box systems, ALPX's CRIMS solution provides clients with exclusive access to their projects, allowing them to track progress in real-time. This innovative approach offers a level of openness that is unparalleled in the industry. Biotech and pharma companies can also remotely oversee experiments, fostering collaboration and providing invaluable insights.

ALPX has significantly improved the frequency and regularity of beamtime. The reliable and regular access to diverse synchrotron facilities is very much appreciated among their clients. ALPX utilizes numerous synchrotrons across Europe, minimizing shutdowns to the point where they are almost non-existent. As a result, clients never experience any delay in the workflow. They can observe the crystals, collaborate with ALPX experts in Grenoble via CRIMS, and swiftly request automated harvesting. The efficient handling of prepared crystals by ALPX ensures timely dispatch to synchrotrons. As a result, the company typically achieves structural outcomes within a few days, marking a significant improvement from previous timelines that spanned weeks.

The excellent technology capabilities enable ALPX to handle a diverse range of targets, encompassing proteins, DNA, biologics (including antibodies), membrane proteins, and even large ternary complexes, often in complex with small molecule binders.

“Clients can even engage with us when their own crystals are ready, and we take care of data collection effectively. Our versatile pipeline is open and flexible, allowing entry at any point,” says Cornaciu-Hoffmann.

An Efficient Team and Process: The Perfect Success Recipe

The key driver of ALPX's success lies in its team and the diverse skill sets within the workforce. The company goes beyond assembling scientists, crystallographers, or project managers; it aims higher by incorporating individuals who can effectively oversee projects, handle lab operations, and even engage in software development. The fusion of scientific expertise with software development in the team fosters a sustainable growth environment. ALPX, in addition, prioritizes continuous training for all team members, ensuring that each person grows and evolves toward their fullest potential.

The team's dedication and efficiency, coupled with the commitment to drive every project toward success, create a synergy that ultimately benefits everyone involved. Some clients have a clear vision of their objectives, but many seek collaborative partners, a sounding board for their ideas. In such cases, the ALPX team steps in as an additional resource. Internally, they hold brainstorming sessions to explore ways to go the extra mile, aiming to achieve groundbreaking outcomes. ALPX highly values client feedback as an invaluable tool for continuous improvement, ensuring the evolution and adaptation of its pipeline to meet clients' needs. Moreover, the team at ALPX takes great joy in clients' success stories, demonstrating the positive impact of their collaboration and contributions to achieving significant milestones in drug discovery. As an example, four months ago, in mid-August, a group reached out to ALPX, expressing frustration after months of working on an exceptionally challenging target without positive results. In a mere three weeks of collaboration, the company achieved a remarkable breakthrough—a co-structure with a covalent inhibitor bound to a crucial target in drug discovery. The client's response was immensely gratifying for ALPX; they acknowledged the milestone achieved together, referring to it as a significant achievement.

Championing a Great Service Model

ALPX has proposed a wide range of services related to Protein X-ray crystallography. The ALPX services were designed to solve the structures of intricate targets - online crystallography being our entry point. The small molecule screening service is available for advanced projects in which the crystallization parameters are established and where the full power of the CrystalDirect technology can be unleashed to optimize throughput and turnover. One natural step and exciting direction to explore was the membrane service, where highly relevant targets are still needed for structural insight. Membrane proteins represent a large and mostly unexplored domain that ALPX is tackling with experienced scientists and top-notch technology. We also provide independent data collection services to facilitate the data acquisition of our clients during shutdown periods that our European or American clients will face in 2024.

ALPX is uniquely and well-placed to approach challenges from multiple perspectives, facilitating the rapid determination of new, high-impact structures, and conducting expert screening of small molecules.

In the coming period, ALPX will continue to grow, adapt and thrive, exploring more uncharted territories to support clients becoming successful in their endeavors.