RESUMEN
Inhibition of the checkpoint protein CTLA-4 by the US-FDA's approved monoclonal antibody ipilimumab has delivered breakthrough therapies against a wide range of cancers, being an important issue for clinical research. To date, many structural properties of this drug have been unveiled. However, the binding energy features of the receptor CTLA-4 in complex with its drug inhibitor, based on crystallographic data, need a deeper understanding. Within this context, by employing quantum chemistry we investigate in silico the binding energy features of the checkpoint protein CTLA-4 in complex with its drug inhibitor, highlighting the most relevant residue-residue interactions, looking for new insights into the mechanisms of pathway blockade to further engineer its affinity and selectivity. Our computational results not only give a better understanding of the binding mechanisms, but also point to an efficient alternative towards the development of antibody-based drugs, leading to new treatments for cancer therapy based upon immunotherapy.
Asunto(s)
Antineoplásicos Inmunológicos/química , Antígeno CTLA-4/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/química , Ipilimumab/química , Secuencia de Aminoácidos , Antineoplásicos Inmunológicos/farmacología , Antígeno CTLA-4/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Ipilimumab/farmacología , Modelos Moleculares , Unión Proteica , Conformación Proteica , TermodinámicaRESUMEN
Cancer is a group of diseases involving disordered growth of abnormal cells with the potential to invade and spread to other parts of the body. Today, immunotherapy is the most efficient treatment, with fewer side effects. Notably, the employment of monoclonal antibodies to inhibit checkpoint proteins, such as CTLA-4, has caused much excitement among cancer immunotherapy researchers. Thus, in-depth analysis through quantum biochemistry and molecular dynamics simulations was performed to understand the complex formed by ipilimumab and its target CTLA-4. Our computational results provide a better understanding of the binding mechanisms and new insights about the CTLA-4: ipilimumab interaction, identifying essential amino acid residues to support the complex. Additionally, we report new interactions such as aromatic-aromatic, aromatic-sulfur, and cation-pi interactions to stabilize the CTLA-4:ipilimumab complex. Finally, quantum biochemistry analyses reveal the most important amino acid residues involved in the CTLA-4:ipilimumab interface, which were used to design synthetic peptides to inhibit CTLA-4. The computational results presented here provide a better understanding of the CTLA-4:ipilimumab binding mechanisms, and can support the development of alternative antibody-based drugs with high relevance in cancer immunotherapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Antígeno CTLA-4/inmunología , Diseño de Fármacos , Inmunoterapia , Ipilimumab/uso terapéutico , Neoplasias/inmunología , Neoplasias/terapia , Péptidos/uso terapéutico , Antígeno CTLA-4/química , Electricidad , Humanos , Ipilimumab/química , Simulación de Dinámica Molecular , Péptidos/química , Unión Proteica , Proteolisis , TermodinámicaRESUMEN
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Asunto(s)
Humanos , Ipilimumab/química , Ipilimumab/uso terapéutico , Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/uso terapéutico , Drogas en Investigación , Aprobación de Drogas , Neoplasias/tratamiento farmacológicoRESUMEN
The programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are negative regulators of T-cell immune function. Removal of these "brakes" in T cells results in increased activation of the immune system and controlling and eradicating tumor. The development of immune checkpoint inhibitors (ICIs) is a revolutionary milestone in tumor immunotherapy. Obtaining the atomic structure of the human immune checkpoint receptor/ICI therapeutic antibody complex is essential for understanding its inhibition mechanism and the rational design of improved biotherapeutics. In this chapter, we describe the methods for efficient production of extracellular domain of human immune checkpoint receptors and Fv fragments of ICI therapeutic antibodies in milligram quantities sufficient for structural studies, taking examples of the PD-1/pembrolizumab Fv and CTLA-4-ipilimumab Fv complexes.
