Challenges for drug development of targeted protein complexes

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Opportunities and challenges for drug development of targeted protein complexes

Opportunities and challenges for drug development of targeted protein complexes. The receptor complex is composed of core receptor proteins and related proteins, which have an important influence on the overall structure, function and positioning of the receptor.

Traditionally, the focus of drug discovery has been to promote or prevent receptor activation by directly targeting receptor proteins. In the receptor family, G protein-coupled receptors (GPCRs) and ligand-gated ion channels (Ligand-gated ion channels, LGICs) receptors are important drug targets, almost containing more than 40% of approved drugs.

For GPCRs and LGICs, receptor proteins and receptor-related proteins (accessory proteins) form complexes through protein-protein interactions (PPIs). The functional characteristics, signal pathways and localization of this receptor complex are often different from a single receptor protein, and its formation is often mediated by several extracellular, intracellular and intracellular PPIs.

Therefore, the pharmacology of the receptor complex Regulation provides an opportunity to target and regulate specific signal pathways. By targeting receptor complexes, disease mechanisms can be regulated more precisely, and more effective drugs with fewer side effects can be found.

Challenges for drug development of targeted protein complexes

The receptor complex is formed by PPIs, but drug discovery that targets PPIs currently faces many challenges.

First, PPIs are usually formed by large interaction surfaces, and there is no defined binding pocket that can accommodate small molecules.
Second, compared with enzymes and receptors, a given PPI lacks endogenous ligands, which makes rational design of modulators more difficult.
Third, the PPI of the receptor complex is usually located in or under the cell membrane, and requires the development of cell permeability, and sometimes blood-brain barrier permeability PPI modulators.

Strategies for targeting receptor complexes

Challenges for drug development of targeted protein complexes

1. Antibodies:

Antibodies and related biological agents are very suitable for binding to large surfaces, with high strength and specificity, and can be used to target some related receptor complexes. The recently approved monoclonal antibodies Erenumab and Erenumab both target Calcitonin receptor-like receptor (CALCRL)-Receptor activity-modifying protein 1, RAMP1 Complex for the treatment of migraine prevention.

The antibody can also target the specific conformation of the receptor complex and stabilize the active or inactive state of the receptor complex. Thanks to technological advances in this field such as hybridoma display and phage display, the number of monoclonal antibodies in clinical trials has increased significantly in recent years. However, because antibodies cannot easily pass through cell membranes or the blood-brain barrier, their use in extracellular PPIs in peripheral tissues is limited.

2. Small molecule modulators:

Through phenotypic screening, the active molecules of the targeted receptor complex can be found. In particular, high-throughput screening (HTS) is widely used to identify small molecule regulation of targeted complexes. Agent. Recognition of active small molecules by HTS requires high-quality compound libraries with diverse structures, and is limited by library capacity and screening analysis methods.

At the same time, HTS also faces defects such as low frequency, low quality hit rate, and false alarms. At present, the discovery of complex small molecules through HTS binding drug optimization is becoming a common way, such as the compound that is being developed for the AMPAR-TARPγ8 complex.

HTS has also derived some variant technologies, such as fragment-based drug discovery, in which “fragments” of small molecules are screened, which can then be used as a starting point for the development of small molecule modulators. DNA-encoded chemical libraries (DELs) are also a variant of HTS, which has the advantage of producing more small molecules than HTS.

The wide application of DELs in the pharmaceutical industry brings hope to the identification of receptor complex modulators. In addition, because DELs can recognize protein binders, DELs can also help construct ligand discovery designs that induce targeted protein degradation of receptor complex components.

3. PPI modulators based on peptides:

In the case of receptor complex regulation involving interacting proteins, small molecules may not be suitable, on the contrary peptides can be used as a good starting point. However, the problem of poor pharmacokinetic properties of peptides leads to the need for more property optimization in the later stage.

Peptide inhibitors often require us to understand the key PPI characteristics, such as based on structural information (from X-ray crystal structure, nuclear magnetic resonance structure, etc.) to guide the design. This inhibitor often mimics the secondary structure of one of the proteins (such as α-helix, β-sheet or β-turn, among which mimic α-helix is the most extensive source of peptide inhibitors), and then uses chemical Cyclization stabilizes its secondary structure to improve binding affinity, metabolic stability and cell permeability.

In the absence of complex structure information, the use of peptide chip technology (such as SPOT) through alanine scanning and deep mutation scanning can systematically explore the structure-activity relationship, identify peptide binding sequences, and form the starting point for inhibitor development.

In addition, some peptide display technologies (such as phage display, ribosome display or mRNA display) can be used to identify and optimize peptide inhibitors. The starting peptides have been optimized through multiple rounds to find high-affinity peptides, which can be further developed into peptide derivatives.

When peptide modulators lack cell permeability, the use of macrocyclization or the method of coupling them with cell-permeable peptides (such as Tat and other cell-penetrating peptides) can improve their ability to enter cells. However, it is worth noting that clinical trials have found that cell penetrating peptides are related to adverse reactions.

Therefore, the development of cell penetrating peptides with excellent performance in the future will be a promising research field.

Challenges for drug development of targeted protein complexes

In terms of targeting the active molecules of the receptor complex, how to rationally design more effective, selective and safe drugs is still in its infancy. In the field of receptor complex drugs, the target of the drug is either the extracellular domain of the receptor or the ion channel domain. In the field of GPCR drugs, the discovery of bias signals provides a way for the development of drugs to regulate specific signaling pathways of GPCRs.

Regarding bias signal body regulation, in addition to regulating GPCRs isoforms and direct interference with G protein and other pharmacological methods, it can also be achieved by targeting receptor-related proteins other than G protein and β-Arrestin protein.

Currently, most studies on receptor complexes regulate the PPI of receptor complexes by preventing or changing protein interactions. It can be expected that increasing PPIs with small molecules to stabilize the receptor complex will be an interesting and very meaningful direction for exploration. In addition, the development of targeted protein degradation ligands is also a promising way to regulate receptor complexes.

The degradation of receptor-associated proteins can provide an alternative and subtle way to interfere with receptor complexes. In short, there are many untapped opportunities for targeting receptor complexes by modulating PPIs.

(source:internet, reference only)

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