[Yan Zou]

Molecular glue is a small molecule that induces or stabilizes interactions between proteins or between proteins and other biomolecules (e.g., DNA, RNA) that would not normally bind or would bind only weakly. These molecules “glue” two or more biomolecules together, often enhancing or disrupting biological functions.

Key Features of Molecular Glues:
1. Small Molecules – Typically <500 Da in size, making them drug-like.
2. Induce or Stabilize Protein-Protein Interactions (PPIs) – They can bring two proteins together or strengthen existing weak interactions.
3. Can Be Natural or Synthetic – Some are naturally occurring (e.g., cyclosporine, rapamycin), while others are designed in labs.
4. Used in Drug Development – They can modulate biological pathways by stabilizing or disrupting protein complexes.

Mechanisms of Action:
– Stabilizing Weak Interactions – Some molecular glues strengthen naturally occurring but transient interactions.
– Inducing Neo-Interactions – They can force two proteins to bind that normally wouldn’t.
– Targeted Protein Degradation – Some (like thalidomide analogs) recruit E3 ubiquitin ligases to mark proteins for degradation (e.g., CRBN-based molecular glues in PROTACs).

Examples of Molecular Glues:
– Immunosuppressants:
– Cyclosporine A – Glues cyclophilin to calcineurin, inhibiting T-cell activation.
– Rapamycin (Sirolimus) – Binds FKBP12 and mTOR, blocking cell growth signals.
– Cancer & Degradation Inducers:
– Lenalidomide & Pomalidomide – Recruit CRBN E3 ligase to degrade transcription factors like IKZF1/3 in multiple myeloma.
– Auxin (plant hormone) – Acts as a natural molecular glue in plants to degrade transcriptional repressors.

Applications:
– Drug Discovery – Especially in targeted protein degradation (e.g., PROTACs).
– Chemical Biology – Used to study protein interactions and pathways.
– Therapeutics – Treating cancer, autoimmune diseases, and neurodegenerative disorders.

Difference Between Molecular Glues & PROTACs:
– Molecular glues are usually smaller and work by directly stabilizing interactions.
– PROTACs (Proteolysis-Targeting Chimeras) are bifunctional molecules that actively recruit E3 ligases to degrade target proteins.

Molecular glues represent a promising area in drug development due to their ability to modulate “undruggable” targets by manipulating protein interactions.

 

Answer generated by DeepSeek.

[Yan Zou]

Here is an answer from DeepSeek:

Activity-Based Protein Profiling (ABPP) is a chemical proteomics technique used to study the functional state of enzymes within complex biological systems. It involves the use of small molecule probes that covalently bind to the active sites of enzymes, allowing for the identification and characterization of these enzymes based on their activity rather than just their abundance.

Here’s a breakdown of how ABPP works:

1. Design of Activity-Based Probes (ABPs): These probes are typically composed of three parts:
– Reactive Group: This part of the probe covalently binds to the active site of the target enzyme. It is often designed to mimic the natural substrate of the enzyme.
– Linker: This part connects the reactive group to the reporter tag. It can vary in length and composition to optimize the binding and detection.
– Reporter Tag: This part allows for the detection and purification of the probe-enzyme complex. Common tags include fluorescent dyes for visualization or biotin for affinity purification.

2.Labeling: The ABPs are introduced to a biological sample (e.g., cell lysates, tissues, or whole organisms). The reactive group of the probe binds to the active site of the target enzymes, forming a covalent bond.

3. Detection and Analysis: After labeling, the enzymes that have bound to the probes can be detected and analyzed. If the reporter tag is a fluorescent dye, the labeled enzymes can be visualized using fluorescence microscopy or gel electrophoresis. If the tag is biotin, the labeled enzymes can be purified using streptavidin beads and subsequently identified using mass spectrometry.

ABPP has several applications, including:
– Target Identification: Identifying the targets of bioactive small molecules or drugs.
– Functional Annotation: Characterizing the activity of enzymes in different biological contexts.
– Drug Discovery: Screening for enzyme inhibitors and understanding their mechanism of action.
– Disease Biomarkers: Discovering enzyme activities that are altered in disease states, which can serve as potential biomarkers or therapeutic targets.

Overall, ABPP provides a powerful tool for understanding the functional proteome and has broad implications in biochemistry, molecular biology, and drug discovery.

[Yan Zou]

Yes, all RNAs are synthesized first as primary transcript. This transcript is processed to produce mature RNA, whether mRNA, rRNA, tRNA, or any other RNA.

[Yan Zou]

Bioinformatics is computational biology.

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