The low specificity of the majority of experimental assays used in drug discovery, as well as, the high attrition rates associated with the initial phases of drug discovery, have led, in many cases, to the late identification of major structural flaws in drug candidates. These failures represent an enormous financial and strategic burden, especially when detected in the later stages of clinical development, where millions of dollars have already been spent with the drug candidate’s development.

Nowadays, companies are seeking to reconcile two essential parameters in the drug discovery field: specificity and high throughput screening (HTS) capacity of the developed assays. HTS is usually linked to in vitro testing, where the simplification of the physiologic process involving the desired disease target allows the improvement of screening times and the simplicity of the developed methods. However, secondary cellular screenings to these in vitro assays frequently demonstrate that the molecules identified in those do not possess the same activity profiles when put in the more complex cellular context. Furthermore, in vitro assays do not allow an immediate measure of citotoxicity characteristics associated with the compounds at test. Being so, the advantageous HTS associated with in vitro assays is not compensated most of the time, as a significant number of the identified molecules are either ineffective or toxic in subsequent development tests. This has been especially true for CNS disorders, where the most commonly used assays have yet failed to deliver a good candidate.

BIOALVO’s proprietary drug discovery platform is based on in vivo assays performed in humanized yeasts. These are modified yeast strains that express the desired human therapeutic target and that have been engineered to possess a DNA sensor, responsive to the presence of this human therapeutic target, which is operable linked to a reporter gene.
Yeast typifies a simple and representative cellular model of the physiological conditions in which the desired target is in the human body. Moreover, it is already scientifically proven that these organisms replicate fundamental cellular aspects that are relevant to neurodegenerative disorders. Additionally, yeast is an organism with very simple, fast and cheap growth conditions and amenable to HTS adaptation. With the proprietary BIOALVO’s yeast platforms, we can overcome the unspecific character of classical in vitro assays while, through its robotic adaptation, we can guarantee the same high throughput needs and low cost available from classical drug discovery programs.

Using our yeast based drug discovery platform we promptly detect major toxicity characteristics associated to the molecules screened, allowing an adequate strategic response that is reflected in reduction of costs associated with future development of condemned candidates. This technology, associated with secondary screening in human cell lines, expressing the desired targets, for hit/lead potency and toxicity confirmation, is a powerful platform indispensable for a fruitful and strong drug discovery programme.
This in-house technology was named GPS D2 (from Global Platform Screening for Drug Discovery).
robot1

Robot Unit costumized for GPS D2 technology

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96 well plate with compounds to be screened

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Schematic representation of GPS Drug Discovery platform

The key advantages of this technology are:
1. Allowance to fail early: compounds with no direct target activity or major toxicity problems are immediately flagged;
2. Better predictability of efficacy than conventional drug screening platforms: prediction of true modulators and their toxic dose in just one screen;
3. Targets are in a physiological relevant and complex environment;
4. Some applications can reveal possible mechanisms of action for our compounds;
5. Eliminates time and cost of target identification/validation prior to screening as it validates drug candidates instead of targets;
6. Efficient, resources-friendly, highly informative, and adaptable to any HTS quantity (HTS ~ 10 000/week at BIOALVO);
7. High quality drug-like hits (not toxic, membrane permeable, biologically/chemically stable…) at a very early stage in a drug development programme;
8. Decreased screening time, resulting in a higher success rate;
9. Selection of hits via biological systems (yeast and human cells) reduces and refines subsequent rodent studies, decreasing the need of animal testing for drug discovery;
10. Especially useful in pioneering disease area’s (CNS, Neurodegeneration, Cancer) due to its adaptability to several targets, allowing to address several groups of diseases.

Based on different requisites of the targets under study BIOALVO developed different screening applications based on its GPS D2 technology.

The screening applications developed so far have the following scope:
• Neurological disorders (Parkinson's, stroke, multiple sclerosis, schizophrenia…)
• Autoimmune disorders (neuroinflamation, allergy, fetal-rejection...)
• Infectious diseases (cerebral malaria, HIV...)
• Cancer
• Age-related diseases (type I and II diabetes…)

Based on core capabilities of the GPS D2 further applications will be developed. To know more about some of the potential applications that can be developed using GPS D2please see list of identified targets. GPS D2 platform is customizable and available for partnering.

Presently BIOALVO has access to a 50.000 compounds library acquired from a USA partner and has an alliance with ICAT - University of Lisbon to access the 208 extracts PharmaBug library based on novel microbial samples from Atlantic hydrothermal vents collection.

Using our unique screening platforms we are currently developing some of small-molecule candidates for applications such as Alzheimer’s, amyloidosis, Huntington’s and other age-related diseases.