Ligands for Surface Receptors

Integrin receptors are responsible for the bidirectional communication between cells. They are exposed on the cell surface and undergo a series of sequential conformational changes upon activation. The integrin αIIbβ3 receptor on platelets recognizes an Arg-Gly-Asp (RGD) motif, leading to activation and subsequent platelet aggregation, an initial step in thrombus formation. Blocking this receptor results in the arrest of the clotting process. Compounds mimicking the RGD motif have been successfully developed as potent fibrinogen receptor antagonists for the therapy of thrombotic events. During inflammatory processes, leukocytes must be stopped and immobilized by sugar-protein interactions with selectins to defend against pathogens. Interfering with the inflammatory cascade with selectin inhibitors can help treat diseases caused by excessive leukocyte infiltration. Viruses gain entry into host cells by docking and subsequently fusing their envelope to the host cell membrane. Peptides such as enfuvirtide can inhibit the fusion process of the HI virus. Influenza is a viral disease caused by influenza viruses. They bind to the host cell via the hemagglutinin surface protein, use the host cell machinery to replicate and, after reassembly, bud from the host cell. Final release from the host cell is catalyzed by neuraminidase, which cleaves the sugar bond between galactose and terminal sialic acid. Antiviral drugs, such as zanamivir and oseltamivir, have been developed to block the catalytic cleavage site of neuraminidase. Oseltamivir uses an aliphatic side chain to improve its bioavailability. This modification causes amino acids near the introduced side chain to rearrange. A resistance mutation prevents this rearrangement and reduces the affinity for oseltamivir. The common cold is caused by rhinoviruses, which belong to the class of non-enveloped, single-stranded RNA picornaviruses. Their capsid, a regular 20-faced icosahedron that encloses the RNA, consists of four surface proteins. They have a structured surface with deep canyons that bind to cellular adhesion proteins. Below the canyon is an elongated pocket that can bind small molecules. These molecules cause a small shift in the canyon, preventing efficient binding to the cell adhesion proteins. The cellular immune system is able to scan cells for the characteristic of being “healthy” or “diseased” through the interacions of major histocompatibility complex (MHC) molecules exposed on the surface and the hypervariable recognition loops of the CD8+ T-cell receptor on T-lymphocytes. Antigen-presenting MHC-I molecules are loaded with 8-10 residue peptide sequences derived from protein degradation in the proteasome. Peptide fragments from foreign (viral attack) or altered proteins are also exposed. To harness cellular immune mechanisms in drug therapy, peptidomimetic surrogates of MHC-exposed peptides have been developed. They stimulate the immune response, e.g. against tumor cells. Hypersensitivity to drugs can occur because drugs also bind to the peptide binding site of MHC molecules, altering the scope of peptide fragments presented. Cells that were previously recognized as the body’s own are then considered foreign or degenerate, and an immune response is initiated. In CAR-T therapy, T-cells are genetically engineered outside the patient’s body to carry additional receptors that recognize specific markers on tumor cells. The cells are then re-administered to the patient and help that the T-cells will reliably find tumor cells and render them to cell death. https://sn.pub/ksv7om