Molecular Therapies

Our ultimate goal is to discover new molecular therapies that may meet as yet unresolved medical needs. In order to achieve this, we use clinically significant information provided by the different biomedical research programs such as new targets and/or mechanisms of action in order to try and promote their translation to clinical practice through the design and development of new targeted molecular therapies.

Once a new target or mechanism of action has been identified, our first objective is the in vivo validation of the new target, from both an efficacy and safety point of view, and to rule out toxicity associated with a new target and/or mode of action.

In addition to minimizing risk through validation of the in vivo target, we offer added value that is crucial to the project through the development of proprietary pharmacological tools. We begin by obtaining an optimized starting point (lead) with which the in vivo efficacy of the target is validated, generating a series of chemicals protected as intellectual property. A protected Markush formula is used to advance the project towards the clinical phases, through which exploration and optimization is carried out until the most appropriate optimized lead is obtained for the clinical phase. Working with intellectual property means that third parties (e.g., pharmaceutical companies) with more experience and capacity can invest in the project and bring it to the patient, our main target.

Thus, the work method followed by the Molecular Therapy Platform is as follows:
 

  • Validation in vitro and in vivo in terms of efficacy and safety of the new targets or mechanisms of action of clinical interest using new molecules: peptides, aptamers and small molecules.

  • Development of proprietary therapeutic agents. New molecules are designed with several options for modifying them (Markush formula) in order to optimize them on multiple levels, so that they can develop and reach the patient.

Implemented approaches

In order to carry out this process, we use the following approaches, which are complementary and allow us to cover a broad spectrum of alternatives:

  • Peptides. Specifically indicated as in vitro chemical probes in therapeutic strategies that involve breaking protein-protein interactions. These constitute an emerging category of therapeutic molecules.

  • Aptamers. These allow for the development of therapeutic agents with high affinity and specificity. In addition, they may be utilized as an effective transport system for small molecules to the interior of the cell.

  • Small molecules. Because of their versatility in multifactorial optimization, their primary activity and pharmacokinetics, these constitute the established approach to drug discovery. Given their limitations in terms of the potential promiscuity of the components and poor efficacy in breaking protein-protein interactions, the two previous strategies function as complements to this one.

Process and associated technologies

Each of the approaches described above has an associated technology that enables further development and implementation:

  • Peptides

    • Design. Computational tools for identifying and defining the optimal sequences to be synthesized.

    • Solid-phase synthesis. Carried out in multiple CIMA synthesis machines. 

    • Medical chemistry strategies for optimizing ADME properties. This is an iterative process.

  • Aptamers

    • Aptamer design and synthesis. These are selected using the SELEX technique (Systematic Evolution of Ligands by Exponential Enrichment), a complex technique that consists of multiple binding, partition and elution processes. The entire process is carried out at CIMA.

  • Small molecules

    • Biological chemistry. Using computational strategies, a virtual trial is carried out in order to prioritize the millions of compounds to be acquired for use as chemical probes in the preliminary validation of the target. 

    • Synthesis. Chemical synthesis is effected once the design has been carried out and the state-of-the-art and intellectual property have been compared.

    • Medical chemistry. Multifactorial optimization of the synthesized molecules with respect to their primary activity and ADME properties. 

In addition, we have a series of general technologies that are used independently of the approach:

  •  Informatics for drug discovery:

    • Molecular modeling and chemoinformatics. 

    • Analysis of intellectual property.

    • CIMA database. Information relating to molecule-target interaction is annotated and audited, along with logistics from the CIMA molecules library and the quality control standards appluied.

  • Bond affinity trials

    • Biophysical (surface plasmon resonance).

    • Biochemical.

  • ADME/Tox trials (carried out at CIMA/University of Navarra or by subcontractors)

    • Solubility

    • P450s

    • Metabolic stability in liver microsomes

    • Permeability (PAMPA)

    • Plasma or tissue (i.e. brain) binding protein

    • Toxicity. Cytotoxicity (e.g. PBMC, THLE-2) and mutagenicity (Ames)

    • Cardiovascular safety: hERG and patch clamp

  • Pharmacokinetics. Bioanalysis of plasma and tissue (LC-MS/MS)

News



"Our goal is to discover new molecular therapies that can meet unresolved medical requirements, based on new targets and/or mechanisms of action provided by the researchers for CIMA and Clínica Universidad de Navarra", Dr. Julen Oyarzabal, Program Director..

Contact

Contact:
Cristina Canciani
Avda. Pío XII, 55
31008 Pamplona
Spain

(+34) 948 194 700 Ext. 2013
canciani@unav.es