Molecular Medicine & Therapeutics
Follow how a biological target is found, how medicines act on it, and why different treatment approaches have different limits.
See how the pieces connect
- Step 1Find a candidatescreen many molecules together
- Step 2Select a binderenrich molecules that recognize a target
- Step 3Antibody medicineuse a selected binder as a treatment design
- Step 4PCSK9 examplea target involved in LDL-receptor control
- Step 5Compare a second approachreduce the target's RNA message instead
PCSK9 offers a useful comparison of treatment strategies. An antibody can bind circulating PCSK9 protein, while an siRNA such as inclisiran acts inside liver cells to reduce PCSK9 production. Both approaches can preserve LDL receptors, but they act at different points in the biology.
Read the supporting reference: PCSK9 inhibition and LDL receptor regulationDifferent medicines act at different levels
Drug discovery is a set of evidence-building routes, not one universal assembly line.
Intervention points
These are alternative approaches; no single medicine follows every branch
- Possible approachCell-surface / secreted proteinOutside the cellAccessible targets can be bound by antibodies; they generally do not cross intact cell membranes.Open record ↗
- Possible approachIntracellular proteinInside the cellSmall molecules can reach some pockets and alter protein activity.Open record ↗
- Possible approachTarget RNANucleus or cytoplasmASOs or siRNAs can change RNA processing or abundance when delivered to the right cells.Open record ↗
- Possible approachMissing enzymeDepends on disease and deliveryEnzyme-replacement approaches can supply a functional enzyme for selected deficiencies.Open record ↗
Test the hypothesis
Each route needs evidence at several biological levels
- Target engagementDid the medicine reach and interact with its intended target?Open record ↗
- measureMechanism and selectivityDid that interaction produce the intended biological change without unacceptable off-target effects?Open record ↗
- test the proposedMeaningful outcomeDo relevant models and clinical studies support benefit and acceptable risk?Open record ↗
These are examples of modality choice. A promising target or screening hit still needs evidence for target engagement, the proposed mechanism, selectivity, delivery, safety, and clinical benefit. A diagram of a candidate strategy does not imply an approved treatment.
siRNA and antisense reach RNA by different routes
Compare AGO2-loaded RNA interference with two distinct antisense mechanisms.
siRNA: guide-directed RNA interference
AGO2 is the catalytic Argonaute in many siRNA-loaded RISC complexes
- siRNACytoplasm after productive deliveryA short double-stranded RNA design; the guide strand is loaded into an RNA-induced silencing complex.Open record ↗
- loads a guide intoRISC with AGO2CytoplasmAn RNA-guided molecular complex; AGO2 can catalyze target cleavage when guide-target pairing supports it.Open record ↗
- base-pairs withTarget mRNACytoplasmA complementary RNA message; accessibility and sequence matching affect targeting.Open record ↗
- can cleave and promote degradation ofRNA interferenceRNA turnoverCleavage is followed by RNA-fragment turnover; silencing is not guaranteed by delivery or binding alone.Open record ↗
ASO gapmer: recruit RNase H1
A DNA-like gap supports RNase H1 cleavage of the paired RNA strand
- Antisense oligonucleotideNucleus or cytoplasm, depending on targetA sequence-designed therapeutic strand; only some chemistries recruit RNase H1.Open record ↗
- hybridizes withTarget mRNANucleus or cytoplasmAn RNA molecule bound by base pairing; target site accessibility matters.Open record ↗
- recruitsRNase H1Nucleus or cytoplasmThe enzyme that cleaves the RNA strand of a compatible RNA–DNA-like hybrid.Open record ↗
- can cleaveRNase H1-dependent ASO cleavageRNA turnoverA gapmer mechanism that can reduce targeted RNA; chemistry and cell delivery constrain activity.Open record ↗
Steric-blocking ASO: change how RNA is used
Possible outcomes depend on which RNA site is covered
- Possible outcomeSteric-blocking ASONucleus or cytoplasmAn ASO can mask a splice-regulatory or translation-related site without recruiting RNase H1.Open record ↗
- Possible outcomeSplicing changeNucleusMasking a pre-mRNA splice site can change exon inclusion; exon skipping is one designed example.Open record ↗
- Possible outcomeTranslation or RNA-stability changeUsually cytoplasmSome steric designs block interactions that affect translation or transcript stability; effects are site- and chemistry-dependent.Open record ↗
The map separates catalytic cleavage from steric blocking. siRNA guide-target pairing and AGO2 support cleavage in many contexts; RNase H1-competent gapmers recruit a different nuclease. Other ASOs can alter splicing, translation, or RNA stability without RNase H1, depending on chemistry and binding site.
How selected lysosomal enzymes reach a lysosome
Follow a mannose-6-phosphate-tagged enzyme through receptor-mediated uptake and endosomal sorting.
Selected M6P-dependent delivery route
The receptor recognizes a carbohydrate tag and internalizes cargo
- M6P-tagged enzymeExtracellular cargoMany soluble lysosomal enzymes carry mannose-6-phosphate; some therapeutic enzymes can use related uptake machinery.Open record ↗
- is recognized byCI-MPR (IGF2R)Cell surface / GolgiA multifunctional receptor that recognizes M6P-tagged cargo; it also binds IGF2.Open record ↗
- can trigger receptor-mediatedEndocytosisPlasma membraneReceptor-bound enzyme can be internalized into membrane-bound compartments.Open record ↗
- delivers cargo intoEndosomeEndosomal systemAn acidic sorting compartment where receptor and cargo fates are regulated.Open record ↗
- can sort cargo towardLysosomeIntracellularA degradative organelle where delivered lysosomal enzymes can function on suitable substrates.Open record ↗
Therapeutic context
The route supports a mechanism question, not a promise of tissue-wide correction
- Read with limitsEnzyme replacement therapyProduct and tissue dependentThe enzyme product, target cell, route of administration, and disease determine whether sufficient activity reaches the affected compartment.Open record ↗
- Read with limitsBlood–brain barrier deliveryTissue access constraintPeripheral uptake does not establish access to the central nervous system; tissue exposure needs separate evidence.Open record ↗
This is a representative M6P-dependent route used by selected soluble lysosomal enzymes and some enzyme-replacement products. Not every enzyme therapy uses this route. Glycan tagging, CI-MPR/IGF2R abundance, cell type, endosomal sorting, and tissue access affect delivery; the diagram does not imply blood–brain barrier passage.
PCSK9 changes how many LDL receptors are reused
Separate the normal LDL-uptake route from PCSK9-driven receptor degradation and two intervention points.
Clear LDL particles
Surface LDL receptors can bind and internalize LDL for clearance
- LDL particleBlood plasmaAn apoB-containing lipoprotein particle carrying cholesterol in circulation.Open record ↗
- bindsLDL receptor (LDLR)Hepatocyte surfaceA cell-surface receptor that captures LDL and is normally recycled after uptake.Open record ↗
- is internalized throughEndocytosis and sortingEndosomal systemThe receptor-cargo complex enters endosomes; cargo and receptor can have different fates.Open record ↗
- contributes toLDL clearanceWhole-body outcomeHepatic LDLR abundance is one determinant of LDL-particle removal from blood.Open record ↗
PCSK9 favors receptor degradation
Bound PCSK9 can alter endosomal sorting away from LDLR recycling
- PCSK9Extracellular / endosomal routeA secreted regulator that binds LDLR and can affect its intracellular fate.Open record ↗
- bindsPCSK9–LDLR complexCell surface / endosomeThe bound receptor-ligand complex can be sorted toward degradation rather than recycling.Open record ↗
- can route towardLysosomeIntracellularThe degradation route lowers the amount of receptor returned to the cell surface.Open record ↗
- reduces receptor recycling and can lowerLDL clearanceWhole-body outcomeFewer available surface receptors can reduce LDL uptake; the magnitude depends on physiological context.Open record ↗
Neutralize extracellular PCSK9
An antibody acts on circulating protein rather than its RNA message
- Anti-PCSK9 antibody strategyExtracellularAntibody medicines can bind extracellular PCSK9 and limit its interaction with LDLR.Open record ↗
- can neutralizePCSK9CirculationThe target protein is neutralized outside the cell; this differs from reducing its synthesis.Open record ↗
- preserving availability ofLDL receptorHepatocyte surfaceMore receptor may remain available for recycling when PCSK9 pressure is reduced.Open record ↗
- which can supportLDL clearanceWhole-body outcomeThe molecular mechanism can increase clearance capacity; clinical outcomes require separate evidence.Open record ↗
Reduce PCSK9 production with siRNA
Inclisiran acts inside liver cells on PCSK9 mRNA
- InclisiranHepatocytesA PCSK9-targeting siRNA drug delivered to liver cells.Open record ↗
- loads its guide intoRISC with AGO2CytoplasmAn RNA-guided complex that can cleave a complementary target transcript.Open record ↗
- targetsPCSK9 mRNAHepatocyte cytoplasmThe hepatic RNA message targeted by the siRNA guide.Open record ↗
- reduces production ofPCSK9Secreted targetLower transcript can lower production of the target protein; amount and duration depend on treatment context.Open record ↗
- which can preserveLDL receptorHepatocyte surfaceReduced PCSK9 can help preserve LDLR availability for reuse.Open record ↗
- supportingLDL clearanceWhole-body outcomeThis pathway-level effect is distinct from an individualized clinical outcome prediction.Open record ↗
In this selected human mechanism, LDLR abundance contributes to hepatic LDL clearance. PCSK9 can favor lysosomal receptor degradation over recycling. Antibodies bind extracellular PCSK9, while inclisiran lowers hepatic PCSK9 mRNA through RNA interference; these are different mechanisms, and this map is not a clinical outcome prediction.
A compound is enriched in a DNA-encoded library selection. What does that result show?
Topics in this branch
Protein Druggability
How well a protein can be reached and modulated by a medicine with useful selectivity and effect.
Explore this idea 02Protein Binding pockets
Regions of a protein surface or interior that can accommodate a molecule and support binding.
Explore this idea 03Target Engagement
Evidence that a candidate medicine binds or otherwise interacts with its intended biological target in a relevant setting.
Explore this idea 04Potency And efficacy
Two different properties: how much drug is needed for an effect and how large an effect the drug can produce.
Explore this idea 05Drug Selectivity
How preferentially a drug affects one target or pathway compared with other biological targets.
Explore this idea 06High-throughput Screening
Automated testing of many candidate molecules in parallel to find compounds with a desired measurable activity.
Explore this idea 07DNA-encoded Libraries
Collections of small molecules tagged with DNA barcodes that record each compound's identity during pooled binding selections.
Explore this idea 08Phage Display
A selection method that links a displayed peptide or antibody fragment to the genetic sequence that encodes it.
Explore this idea 09Therapeutic Antibodies
Medicines made from antibodies that recognize targets such as receptors, soluble proteins, or cell-surface markers.
Explore this idea 10Molecular Glues
Small molecules that stabilize or create an interaction between proteins, changing the function or fate of one or both partners.
Explore this idea 11How Kinase inhibitors work
Kinase inhibitors can bind different structural states or sites and interfere with phosphorylation signaling.
Explore this idea 12Resistance To kinase inhibitors
Tumor cells can restore signaling or alter drug binding so a kinase inhibitor loses effect.
Explore this idea 13BRAF V600E and MAPK signaling
A recurrent BRAF variant that can drive MAPK-pathway signaling and create a context-dependent drug target.
Explore this idea 14Antisense Oligonucleotides
Short synthetic nucleic-acid strands designed to bind a selected RNA sequence and alter its processing or use.
Explore this idea 15siRNA Therapeutics
Short double-stranded RNAs that guide cellular RNA-interference machinery to a complementary target RNA.
Explore this idea 16RNA Interference
A cellular process in which small RNAs guide protein complexes to reduce or regulate matching RNA molecules.
Explore this idea 17RNA-induced Silencing complex
A protein complex that uses a guide RNA to recognize and regulate complementary target RNAs.
Explore this idea 18RNase H1
An enzyme that recognizes RNA–DNA hybrids and can cleave the RNA strand, a mechanism used by some antisense drugs.
Explore this idea 19Exon Skipping
A splicing strategy that omits a selected exon from pre-mRNA, sometimes restoring the reading frame of a disease-associated transcript.
Explore this idea 20Delivering Therapeutic oligonucleotides
Getting an antisense or siRNA drug into the right tissue, cell, and intracellular compartment.
Explore this idea 21Endosomal Escape
The release of internalized therapeutic molecules from endosomes into the cytoplasm or other site where their target resides.
Explore this idea 22Duchenne Muscular dystrophy
A genetic muscle disease caused by DMD variants that disrupt production of functional dystrophin.
Explore this idea 23SOD1-targeted Antisense research
An example of using an antisense drug to reduce RNA from a disease-associated gene rather than inhibit its protein product.
Explore this idea 24Cholesterol Homeostasis
The balance of cholesterol synthesis, uptake, transport, and removal across tissues.
Explore this idea 25HMG-CoA Reductase
A rate-controlling enzyme in the mevalonate pathway and the molecular target of statin medicines.
Explore this idea 26How Statins lower cholesterol
Statins inhibit HMG-CoA reductase and can increase hepatic uptake of LDL from the circulation.
Explore this idea 27LDL Receptor
A cell-surface receptor that binds LDL particles and helps cells, especially liver cells, remove them from circulation.
Explore this idea 28PCSK9
A protein that can promote LDL-receptor degradation and thereby influence LDL cholesterol levels.
Explore this idea 29Inclisiran And PCSK9 RNA interference
A PCSK9-targeting siRNA example that reduces production of the PCSK9 protein in the liver.
Explore this idea 30Enzyme Replacement therapy
Treatment with a manufactured enzyme to replace or supplement activity that is deficient in a particular disease.
Explore this idea 31Lysosomal Storage disorders
Inherited conditions in which lysosomal enzyme or transporter defects disrupt breakdown and recycling of cellular material.
Explore this idea 32Mannose-6-phosphate Lysosomal targeting
A sorting signal used by many soluble lysosomal enzymes to reach lysosomes through receptor-mediated trafficking.
Explore this idea 33Crossing The blood–brain barrier
A delivery challenge because many therapeutic proteins and other large molecules do not readily enter the brain from blood.
Explore this idea 34Substrate Reduction therapy
A strategy that lowers production of a material that accumulates when its breakdown pathway is impaired.
Explore this idea 35Gaucher Disease
An inherited lysosomal disorder associated with reduced glucocerebrosidase activity and accumulation of its lipid substrate.
Explore this idea 36KRAS G12C
A KRAS variant that replaces glycine at position 12 with cysteine and creates a chemically addressable feature in the protein.
Explore this idea 37Covalent KRAS inhibition
A drug strategy that forms a covalent bond with a mutant cysteine in KRAS G12C to inhibit selected KRAS states.
Explore this idea 38Acquired Drug resistance
A reduction in drug response that develops as cells or tumors adapt under treatment pressure.
Explore this idea 39RNase H1-Dependent ASO Cleavage
A gapmer antisense oligonucleotide binds a complementary RNA sequence and recruits RNase H1 to cleave the RNA strand of the hybrid.
Explore this idea 40Steric-Blocking ASO Mechanisms
An antisense oligonucleotide binds RNA and blocks access by selected molecular partners, potentially changing splicing, translation, or RNA stability without RNase H1 cleavage.
Explore this idea 41Mannose-6-Phosphate
A carbohydrate phosphate tag recognized by mannose-6-phosphate receptors on many soluble lysosomal enzyme cargos.
Explore this idea 42LDL Clearance and PCSK9
An LDLR trafficking route that helps clear LDL particles from circulation and is regulated by PCSK9.
Explore this idea 43LDL Particle
A circulating lipoprotein particle that carries cholesterol and is recognized by LDL receptors through apolipoprotein B-100.
Explore this ideaRNA Targeting Routes
siRNA Therapeutics
Short double-stranded RNAs that guide cellular RNA-interference machinery to a complementary target RNA.
Open record Molecular complexRNA-induced Silencing complex
A protein complex that uses a guide RNA to recognize and regulate complementary target RNAs.
Open record ProteinAGO2
The catalytic Argonaute component of many siRNA-loaded RISC complexes. Cleavage depends on guide-target pairing, RNA accessibility, and the relevant cellular context.
Open record MoleculeMessenger RNA (mRNA)
An RNA molecule that can carry a protein-coding message and can also be regulated by small RNAs or antisense oligonucleotides.
Open record TherapyAntisense Oligonucleotides
Short synthetic nucleic-acid strands designed to bind a selected RNA sequence and alter its processing or use.
Open record ProcessRNase H1-Dependent ASO Cleavage
A gapmer antisense oligonucleotide binds a complementary RNA sequence and recruits RNase H1 to cleave the RNA strand of the hybrid.
Open record ProcessSteric-Blocking ASO Mechanisms
An antisense oligonucleotide binds RNA and blocks access by selected molecular partners, potentially changing splicing, translation, or RNA stability without RNase H1 cleavage.
Open recordLysosomal Enzyme Delivery
Mannose-6-phosphate Lysosomal targeting
A sorting signal used by many soluble lysosomal enzymes to reach lysosomes through receptor-mediated trafficking.
Open record MoleculeMannose-6-Phosphate
A carbohydrate phosphate tag recognized by mannose-6-phosphate receptors on many soluble lysosomal enzyme cargos.
Open record ProteinCI-MPR (IGF2R)
A multifunctional receptor that binds mannose-6-phosphate-tagged cargo and participates in trafficking selected lysosomal enzymes. This is one route among several, and uptake depends on cargo and cell context.
Open record ProcessEndocytosis
A family of processes that internalize extracellular material or plasma-membrane components into membrane-bound vesicles.
Open record Cell componentEndosome
A membrane-bound sorting compartment that receives endocytosed cargo and routes it for recycling, further transport, or degradation.
Open record Cell componentLysosome
An acidic compartment where enzymes digest selected cellular material for recycling and other functions.
Open recordLDL Receptor Clearance
LDL Clearance and PCSK9
An LDLR trafficking route that helps clear LDL particles from circulation and is regulated by PCSK9.
Open record Multi-protein complexPCSK9–LDLR Complex
A receptor–ligand complex formed when PCSK9 binds LDLR. This interaction can change receptor trafficking and favor lysosomal degradation rather than recycling.
Open record ProteinPCSK9
A protein that can promote LDL-receptor degradation and thereby influence LDL cholesterol levels.
Open record ProteinLDL Receptor
A cell-surface receptor that binds LDL particles and helps cells, especially liver cells, remove them from circulation.
Open record Molecular complexLDL Particle
A circulating lipoprotein particle that carries cholesterol and is recognized by LDL receptors through apolipoprotein B-100.
Open record DrugInclisiran And PCSK9 RNA interference
A PCSK9-targeting siRNA example that reduces production of the PCSK9 protein in the liver.
Open record TherapyTherapeutic Antibodies
Medicines made from antibodies that recognize targets such as receptors, soluble proteins, or cell-surface markers.
Open record