Podcast
Questions and Answers
Considering the challenges associated with peptide and protein drugs, which of the following enzymatic activities would LEAST likely contribute to the degradation of a peptide-based therapeutic administered intravenously?
Considering the challenges associated with peptide and protein drugs, which of the following enzymatic activities would LEAST likely contribute to the degradation of a peptide-based therapeutic administered intravenously?
- Dipeptidyl carboxypeptidases sequentially cleaving dipeptides from the C-terminus
- Carboxypeptidases acting on the C-terminal residue
- Aminopeptidases removing amino acids from the N-terminal end
- Endopeptidases within erythrocytes exhibiting broad substrate specificity (correct)
Given the enzymatic specificities within the gastrointestinal (GI) tract, which strategy would MOST effectively protect a peptide drug from degradation in BOTH the stomach and the small intestine?
Given the enzymatic specificities within the gastrointestinal (GI) tract, which strategy would MOST effectively protect a peptide drug from degradation in BOTH the stomach and the small intestine?
- Modifying the peptide to contain only amino acids with small, sterically unhindered side chains
- Encapsulating the peptide in a pH-sensitive polymer that dissolves only in the small intestine.
- Formulating the peptide with a competitive inhibitor of trypsin.
- Replacing all L-amino acids with their D-amino acid counterparts. (correct)
A novel peptide therapeutic is designed to target a receptor in the central nervous system. Considering the various strategies to enhance its bioavailability, which approach would MOST directly address the challenge of poor passage through lipid membranes?
A novel peptide therapeutic is designed to target a receptor in the central nervous system. Considering the various strategies to enhance its bioavailability, which approach would MOST directly address the challenge of poor passage through lipid membranes?
- Replacing selected L-amino acids with D-amino acids.
- Modifying key cleavage sites to secondary amides.
- Incorporating lipophilic moieties into non-pharmacophoric regions of the peptide. (correct)
- Co-administration with protease inhibitors.
In the context of peptidomimetic design, which of the following modifications would be MOST likely to confer resistance to enzymatic hydrolysis while preserving the essential binding interactions with the target receptor?
In the context of peptidomimetic design, which of the following modifications would be MOST likely to confer resistance to enzymatic hydrolysis while preserving the essential binding interactions with the target receptor?
Considering the diverse routes of administration for peptide drugs, which route would MOST likely result in the HIGHEST percentage of dose absorbed for a poorly stable peptide, assuming no additional formulation strategies are employed?
Considering the diverse routes of administration for peptide drugs, which route would MOST likely result in the HIGHEST percentage of dose absorbed for a poorly stable peptide, assuming no additional formulation strategies are employed?
A research team aims to develop a peptidomimetic to inhibit a protease. Which design strategy would be MOST effective in achieving competitive inhibition?
A research team aims to develop a peptidomimetic to inhibit a protease. Which design strategy would be MOST effective in achieving competitive inhibition?
When designing peptidomimetics with unnatural amino acids, what is the MOST critical consideration for maintaining target binding affinity?
When designing peptidomimetics with unnatural amino acids, what is the MOST critical consideration for maintaining target binding affinity?
To enhance the proteolytic stability of a peptide therapeutic, a medicinal chemist proposes N-methylation at a specific amide bond. What is the MOST likely rationale for this modification?
To enhance the proteolytic stability of a peptide therapeutic, a medicinal chemist proposes N-methylation at a specific amide bond. What is the MOST likely rationale for this modification?
In the context of 'scaffold mimics,' such as RGD-based peptidomimetics, what is the MOST crucial design objective?
In the context of 'scaffold mimics,' such as RGD-based peptidomimetics, what is the MOST crucial design objective?
A research group is designing a peptidomimetic somatostatin agonist. Which characteristic would be MOST important for the peptidomimetic to effectively mimic somatostatin's function?
A research group is designing a peptidomimetic somatostatin agonist. Which characteristic would be MOST important for the peptidomimetic to effectively mimic somatostatin's function?
What is the MOST significant advantage of using combinatorial chemistry in the context of peptidomimetic drug discovery?
What is the MOST significant advantage of using combinatorial chemistry in the context of peptidomimetic drug discovery?
In the design of HIV protease inhibitors, what is the PRIMARY rationale for targeting the active site of the protease with peptidomimetic molecules?
In the design of HIV protease inhibitors, what is the PRIMARY rationale for targeting the active site of the protease with peptidomimetic molecules?
Considering the mechanism of action of HIV protease, what is the function of the bound water molecule in the active site during proteolysis?
Considering the mechanism of action of HIV protease, what is the function of the bound water molecule in the active site during proteolysis?
A medicinal chemist is designing a transition state analogue inhibitor for an aspartyl protease. What characteristic is MOST crucial for the analogue to mimic the transition state effectively?
A medicinal chemist is designing a transition state analogue inhibitor for an aspartyl protease. What characteristic is MOST crucial for the analogue to mimic the transition state effectively?
Given the structure of Saquinavir, what is the MOST likely role of the quinoline moiety (S3 subsite) in its interaction with HIV protease?
Given the structure of Saquinavir, what is the MOST likely role of the quinoline moiety (S3 subsite) in its interaction with HIV protease?
Regarding the ADME properties of peptide drugs, which statement is LEAST accurate?
Regarding the ADME properties of peptide drugs, which statement is LEAST accurate?
Which of the following is NOT used as an approach to modify the peptide backbone in peptidomimetic design?
Which of the following is NOT used as an approach to modify the peptide backbone in peptidomimetic design?
What is the key difference between azapeptides, azatides, and peptoids?
What is the key difference between azapeptides, azatides, and peptoids?
Elastase cleaves at small, sterically unhindered residues (Ala, Gly & Ser). Which of these peptides would be cleaved most rapidly by elastase:
Elastase cleaves at small, sterically unhindered residues (Ala, Gly & Ser). Which of these peptides would be cleaved most rapidly by elastase:
What is the MOST accurate description of the role of proline in decreasing proteolysis?
What is the MOST accurate description of the role of proline in decreasing proteolysis?
Which of the following statements BEST captures the essence of rational drug design in the context of peptidomimetic development?
Which of the following statements BEST captures the essence of rational drug design in the context of peptidomimetic development?
What key property differentiates pseudopeptides from conventional peptides?
What key property differentiates pseudopeptides from conventional peptides?
Considering the challenges related to oral administration of peptide drugs, which of the following strategies would be LEAST effective in improving oral bioavailability?
Considering the challenges related to oral administration of peptide drugs, which of the following strategies would be LEAST effective in improving oral bioavailability?
Leuprolide is an analogue of gonadotropin-releasing hormone (GnRH). Given its route of administration and percentage dose absorbed, how is it BEST administered?
Leuprolide is an analogue of gonadotropin-releasing hormone (GnRH). Given its route of administration and percentage dose absorbed, how is it BEST administered?
Considering the enzymatic degradation pathways of peptide drugs, which of the following modifications would MOST effectively prevent both N-terminal and C-terminal degradation?
Considering the enzymatic degradation pathways of peptide drugs, which of the following modifications would MOST effectively prevent both N-terminal and C-terminal degradation?
Given the challenges of oral bioavailability for peptide drugs, which formulation strategy would MOST effectively address BOTH enzymatic degradation and poor membrane permeability?
Given the challenges of oral bioavailability for peptide drugs, which formulation strategy would MOST effectively address BOTH enzymatic degradation and poor membrane permeability?
In designing a peptidomimetic to inhibit protein-protein interaction, what strategy would MOST effectively disrupt the hydrophobic effect driving the interaction while maintaining specificity?
In designing a peptidomimetic to inhibit protein-protein interaction, what strategy would MOST effectively disrupt the hydrophobic effect driving the interaction while maintaining specificity?
A research team is developing a peptidomimetic agonist for a G protein-coupled receptor (GPCR). Considering the complexities of GPCR activation, which design strategy would be MOST critical for achieving sustained receptor activation and downstream signaling?
A research team is developing a peptidomimetic agonist for a G protein-coupled receptor (GPCR). Considering the complexities of GPCR activation, which design strategy would be MOST critical for achieving sustained receptor activation and downstream signaling?
Considering the challenges associated with targeting intracellular protein-protein interactions with peptidomimetics, which strategy would MOST effectively enhance cellular uptake while maintaining target specificity?
Considering the challenges associated with targeting intracellular protein-protein interactions with peptidomimetics, which strategy would MOST effectively enhance cellular uptake while maintaining target specificity?
In the context of designing peptidomimetic inhibitors for metalloproteases, which of the following functional groups would MOST effectively coordinate with the catalytic metal ion?
In the context of designing peptidomimetic inhibitors for metalloproteases, which of the following functional groups would MOST effectively coordinate with the catalytic metal ion?
Given the structural diversity of β-turns in peptides, which peptidomimetic scaffold would MOST effectively mimic a Type VIa β-turn conformation?
Given the structural diversity of β-turns in peptides, which peptidomimetic scaffold would MOST effectively mimic a Type VIa β-turn conformation?
Considering the role of specific water molecules in enzyme active sites, which peptidomimetic design strategy would be MOST effective in mimicking the hydrogen bonding network of a catalytically essential water molecule?
Considering the role of specific water molecules in enzyme active sites, which peptidomimetic design strategy would be MOST effective in mimicking the hydrogen bonding network of a catalytically essential water molecule?
In the context of developing peptidomimetic inhibitors of the MDM2-p53 interaction, which strategy would be MOST effective in mimicking the key hydrophobic residues of p53 that bind to the MDM2 hydrophobic pocket?
In the context of developing peptidomimetic inhibitors of the MDM2-p53 interaction, which strategy would be MOST effective in mimicking the key hydrophobic residues of p53 that bind to the MDM2 hydrophobic pocket?
When designing a peptidomimetic to disrupt a signaling pathway mediated by protein phosphorylation, which modification would MOST effectively mimic the phosphorylated residue?
When designing a peptidomimetic to disrupt a signaling pathway mediated by protein phosphorylation, which modification would MOST effectively mimic the phosphorylated residue?
Considering the dynamic nature of protein conformations, which peptidomimetic design approach would be MOST effective in targeting an intrinsically disordered protein (IDP)?
Considering the dynamic nature of protein conformations, which peptidomimetic design approach would be MOST effective in targeting an intrinsically disordered protein (IDP)?
Given the role of glycosylation in modulating protein function, which peptidomimetic strategy would be MOST effective in mimicking a specific glycan moiety?
Given the role of glycosylation in modulating protein function, which peptidomimetic strategy would be MOST effective in mimicking a specific glycan moiety?
In the context of designing peptidomimetic inhibitors for epigenetic targets such as histone deacetylases (HDACs), which functional group is MOST critical for interacting with the catalytic zinc ion in the HDAC active site?
In the context of designing peptidomimetic inhibitors for epigenetic targets such as histone deacetylases (HDACs), which functional group is MOST critical for interacting with the catalytic zinc ion in the HDAC active site?
Considering the challenges of crossing the blood-brain barrier (BBB) with peptide therapeutics, which strategy would be MOST effective in enhancing BBB permeability while maintaining target specificity?
Considering the challenges of crossing the blood-brain barrier (BBB) with peptide therapeutics, which strategy would be MOST effective in enhancing BBB permeability while maintaining target specificity?
In designing a peptidomimetic to inhibit a protein kinase, which strategy would be MOST effective in mimicking the ATP-binding site while maintaining selectivity over other kinases?
In designing a peptidomimetic to inhibit a protein kinase, which strategy would be MOST effective in mimicking the ATP-binding site while maintaining selectivity over other kinases?
When developing a peptidomimetic to modulate immune responses, which strategy would be MOST effective in mimicking a T-cell epitope presented on MHC molecules?
When developing a peptidomimetic to modulate immune responses, which strategy would be MOST effective in mimicking a T-cell epitope presented on MHC molecules?
In the context of designing peptidomimetic antagonists for chemokine receptors, which modification would MOST effectively block receptor activation without inducing downstream signaling?
In the context of designing peptidomimetic antagonists for chemokine receptors, which modification would MOST effectively block receptor activation without inducing downstream signaling?
Considering the challenges of targeting RNA with small molecules, which peptidomimetic strategy would be MOST effective in recognizing and binding to a specific RNA secondary structure?
Considering the challenges of targeting RNA with small molecules, which peptidomimetic strategy would be MOST effective in recognizing and binding to a specific RNA secondary structure?
When designing a peptidomimetic to inhibit viral entry, which strategy would be MOST effective in mimicking the viral fusion peptide and preventing membrane fusion?
When designing a peptidomimetic to inhibit viral entry, which strategy would be MOST effective in mimicking the viral fusion peptide and preventing membrane fusion?
In the context of developing peptidomimetic inhibitors for bacterial quorum sensing, which strategy would be MOST effective in disrupting the bacterial communication system?
In the context of developing peptidomimetic inhibitors for bacterial quorum sensing, which strategy would be MOST effective in disrupting the bacterial communication system?
Considering the role of protein misfolding in neurodegenerative diseases, which peptidomimetic strategy would be MOST effective in preventing the aggregation of amyloid-beta peptides?
Considering the role of protein misfolding in neurodegenerative diseases, which peptidomimetic strategy would be MOST effective in preventing the aggregation of amyloid-beta peptides?
When designing a peptidomimetic to inhibit a ubiquitin ligase, which strategy would be MOST effective in blocking the interaction between the E3 ubiquitin ligase and its substrate?
When designing a peptidomimetic to inhibit a ubiquitin ligase, which strategy would be MOST effective in blocking the interaction between the E3 ubiquitin ligase and its substrate?
In the context of developing peptidomimetic inhibitors for immune checkpoint proteins such as PD-1 and CTLA-4, which strategy would be MOST effective in blocking their interaction with their respective ligands?
In the context of developing peptidomimetic inhibitors for immune checkpoint proteins such as PD-1 and CTLA-4, which strategy would be MOST effective in blocking their interaction with their respective ligands?
Considering the challenges of targeting protein aggregates in lysosomes, which peptidomimetic strategy would be MOST effective in enhancing lysosomal degradation of aggregated proteins?
Considering the challenges of targeting protein aggregates in lysosomes, which peptidomimetic strategy would be MOST effective in enhancing lysosomal degradation of aggregated proteins?
Describe the mechanistic rationale behind replacing L-amino acids with their D-counterparts to decrease proteolysis of peptide drugs, considering enzyme-substrate interactions in chiral environments.
Describe the mechanistic rationale behind replacing L-amino acids with their D-counterparts to decrease proteolysis of peptide drugs, considering enzyme-substrate interactions in chiral environments.
Elaborate on the practical, synthetic, and regulatory challenges associated with large-scale manufacturing of peptide drugs incorporating multiple unnatural amino acids.
Elaborate on the practical, synthetic, and regulatory challenges associated with large-scale manufacturing of peptide drugs incorporating multiple unnatural amino acids.
Discuss the implications of 'backbone grafting' in peptidomimetic design on the conformational space sampled by the resulting molecule, and its subsequent effect on receptor selectivity and off-target pharmacology.
Discuss the implications of 'backbone grafting' in peptidomimetic design on the conformational space sampled by the resulting molecule, and its subsequent effect on receptor selectivity and off-target pharmacology.
Explain why $N$-methylation at key cleavage sites leads to decreased proteolysis, detailing the structural and electronic effects that contribute to this phenomenon.
Explain why $N$-methylation at key cleavage sites leads to decreased proteolysis, detailing the structural and electronic effects that contribute to this phenomenon.
Describe the role of lipophilic modification of polar, non-pharmacophoric regions of peptide drugs in enhancing bioavailability, accounting for both transcellular and paracellular transport mechanisms.
Describe the role of lipophilic modification of polar, non-pharmacophoric regions of peptide drugs in enhancing bioavailability, accounting for both transcellular and paracellular transport mechanisms.
Propose a peptidomimetic design strategy to target a protein-protein interaction (PPI) known to be 'undruggable,' outlining specific chemical modifications and rationale for optimized binding affinity and drug-like properties.
Propose a peptidomimetic design strategy to target a protein-protein interaction (PPI) known to be 'undruggable,' outlining specific chemical modifications and rationale for optimized binding affinity and drug-like properties.
Critically evaluate the use of in silico methods, such as molecular dynamics simulations and free energy perturbation calculations, in predicting the proteolytic stability of modified peptide drugs a priori.
Critically evaluate the use of in silico methods, such as molecular dynamics simulations and free energy perturbation calculations, in predicting the proteolytic stability of modified peptide drugs a priori.
Explain the concept of 'conformational restriction' in the context of peptidomimetic design, and provide a detailed example of how strategic cyclization can modulate both potency and selectivity.
Explain the concept of 'conformational restriction' in the context of peptidomimetic design, and provide a detailed example of how strategic cyclization can modulate both potency and selectivity.
Discuss the challenges and strategies for designing orally bioavailable peptide drugs, addressing both enzymatic degradation and poor membrane permeability.
Discuss the challenges and strategies for designing orally bioavailable peptide drugs, addressing both enzymatic degradation and poor membrane permeability.
Describe advanced drug delivery system principles such as receptor-mediated endocytosis or stimuli-responsive release, and how they could be adapted for targeted delivery of peptide or peptidomimetic drugs to specific tissues or cells.
Describe advanced drug delivery system principles such as receptor-mediated endocytosis or stimuli-responsive release, and how they could be adapted for targeted delivery of peptide or peptidomimetic drugs to specific tissues or cells.
What are the key differences in substrate specificity between trypsin, chymotrypsin, and elastase, and how are these differences exploited in enzymatic synthesis or degradation studies of peptide drugs?
What are the key differences in substrate specificity between trypsin, chymotrypsin, and elastase, and how are these differences exploited in enzymatic synthesis or degradation studies of peptide drugs?
How does the compact, globular tertiary structure of full-sized proteins affect their resistance to enzymatic degradation compared to smaller peptides and polypeptides?
How does the compact, globular tertiary structure of full-sized proteins affect their resistance to enzymatic degradation compared to smaller peptides and polypeptides?
What are the mechanistic implications of designing a non-hydrolysable peptide mimic for an enzyme target and how does this strategy affect the enzyme's catalytic cycle?
What are the mechanistic implications of designing a non-hydrolysable peptide mimic for an enzyme target and how does this strategy affect the enzyme's catalytic cycle?
Describe the role and mechanism of action of carboxypeptidases, dipeptidyl carboxypeptidases, aminopeptidases, and amidases in the context of peptide drug metabolism.
Describe the role and mechanism of action of carboxypeptidases, dipeptidyl carboxypeptidases, aminopeptidases, and amidases in the context of peptide drug metabolism.
Discuss the advantages and disadvantages of Solid Phase Organic Synthesis (SPOS) in the context of producing diverse libraries of peptidomimetics, compared to traditional solution-phase synthesis.
Discuss the advantages and disadvantages of Solid Phase Organic Synthesis (SPOS) in the context of producing diverse libraries of peptidomimetics, compared to traditional solution-phase synthesis.
Compare and contrast the use of $\beta$-turn mimetics, $\alpha$-helix mimetics, and $\beta$-sheet mimetics in stabilizing specific protein conformations for therapeutic purposes, focusing on mechanisms of action and limitations.
Compare and contrast the use of $\beta$-turn mimetics, $\alpha$-helix mimetics, and $\beta$-sheet mimetics in stabilizing specific protein conformations for therapeutic purposes, focusing on mechanisms of action and limitations.
Describe the chemical principles behind 'stapled peptides,' and explain how these modifications enhance the therapeutic potential of peptides targeting intracellular protein-protein interactions.
Describe the chemical principles behind 'stapled peptides,' and explain how these modifications enhance the therapeutic potential of peptides targeting intracellular protein-protein interactions.
Explain the role of Arginine-Glycine-Aspartic acid (RGD) sequence in cellular adhesion and how RGD-based peptidomimetics are designed to modulate integrin-mediated cell interactions in diseases such as cancer and thrombosis.
Explain the role of Arginine-Glycine-Aspartic acid (RGD) sequence in cellular adhesion and how RGD-based peptidomimetics are designed to modulate integrin-mediated cell interactions in diseases such as cancer and thrombosis.
What are 'azapeptides,' 'azatides,' and 'peptoids,' and how do these structural modifications impact the proteolytic stability and conformational properties of peptide drugs?
What are 'azapeptides,' 'azatides,' and 'peptoids,' and how do these structural modifications impact the proteolytic stability and conformational properties of peptide drugs?
Explain how transition state analogue inhibitors of HIV protease function at a molecular level, and describe the key structural features that contribute to their high binding affinity and specificity.
Explain how transition state analogue inhibitors of HIV protease function at a molecular level, and describe the key structural features that contribute to their high binding affinity and specificity.
Describe the potential benefits and drawbacks of 'retro-inverso' peptides in drug design, considering their altered chirality and impact on enzymatic recognition and receptor binding.
Describe the potential benefits and drawbacks of 'retro-inverso' peptides in drug design, considering their altered chirality and impact on enzymatic recognition and receptor binding.
Detail the mechanisms by which protease inhibitors and permeation enhancers can be co-administered to improve nasal delivery of peptide drugs, addressing both enzymatic degradation and epithelial barrier permeability.
Detail the mechanisms by which protease inhibitors and permeation enhancers can be co-administered to improve nasal delivery of peptide drugs, addressing both enzymatic degradation and epithelial barrier permeability.
Explain how the displayed structures of phenylalanine analogues can influence both their conformational flexibility and lipophilicity, and how these properties affect their interactions with biological targets.
Explain how the displayed structures of phenylalanine analogues can influence both their conformational flexibility and lipophilicity, and how these properties affect their interactions with biological targets.
Describe strategies for rationally designing glucose scaffold analogues of cyclic peptides, focusing on maintaining similar spatial arrangements of key pharmacophoric groups, and predicting their effects on receptor binding.
Describe strategies for rationally designing glucose scaffold analogues of cyclic peptides, focusing on maintaining similar spatial arrangements of key pharmacophoric groups, and predicting their effects on receptor binding.
Explain how combinatorial chemistry and rational drug design differ in their approaches to discovering peptide and peptidomimetic drugs, and discuss the advantages and limitations of each method.
Explain how combinatorial chemistry and rational drug design differ in their approaches to discovering peptide and peptidomimetic drugs, and discuss the advantages and limitations of each method.
The compact ______ nature of many full-sized proteins increases their resistance to degradation compared to smaller proteins and polypeptides.
The compact ______ nature of many full-sized proteins increases their resistance to degradation compared to smaller proteins and polypeptides.
Key metabolic enzymes such as carboxypeptidases, dipeptidyl carboxypeptidases, aminopeptidases, and ______ are responsible for peptide and protein breakdown.
Key metabolic enzymes such as carboxypeptidases, dipeptidyl carboxypeptidases, aminopeptidases, and ______ are responsible for peptide and protein breakdown.
Replacing selected L-amino acids with D-amino acids can increase resistance to ______ while potentially maintaining biological activity.
Replacing selected L-amino acids with D-amino acids can increase resistance to ______ while potentially maintaining biological activity.
One strategy to decrease proteolysis involves changing primary amides to secondary amides, often through N-______ or the replacement of a natural residue with proline.
One strategy to decrease proteolysis involves changing primary amides to secondary amides, often through N-______ or the replacement of a natural residue with proline.
The oral administration of peptides is limited due to enzymatic ______ of peptide bonds within the gastrointestinal tract, kidneys, and liver.
The oral administration of peptides is limited due to enzymatic ______ of peptide bonds within the gastrointestinal tract, kidneys, and liver.
Modifying peptides to be less polar is crucial for improving their passage through ______ membranes and increasing bioavailability.
Modifying peptides to be less polar is crucial for improving their passage through ______ membranes and increasing bioavailability.
[Blank] mimic the structures of particular peptides to fool a receptor into thinking it is binding with the actual peptide and induce the same biological effect.
[Blank] mimic the structures of particular peptides to fool a receptor into thinking it is binding with the actual peptide and induce the same biological effect.
For enzymes, a non-hydrolysable peptide mimic that binds to the active site would serve as a ______ inhibitor of the hydrolysis of the real substrate.
For enzymes, a non-hydrolysable peptide mimic that binds to the active site would serve as a ______ inhibitor of the hydrolysis of the real substrate.
Replacing non-pharmacophoric polar sections of a natural molecule with ______ moieties can often increase membrane permeation and bioavailability.
Replacing non-pharmacophoric polar sections of a natural molecule with ______ moieties can often increase membrane permeation and bioavailability.
The use of unnatural amino acids in peptidomimetics can lead to different conformational restriction profiles and varying degrees of ______.
The use of unnatural amino acids in peptidomimetics can lead to different conformational restriction profiles and varying degrees of ______.
Structural extension in peptidomimetics reinforces interactions with the target binding site, potentially leading to ______ affinity compared to the natural substrate.
Structural extension in peptidomimetics reinforces interactions with the target binding site, potentially leading to ______ affinity compared to the natural substrate.
The one letter code RGD represents the amino acid sequence ______, which is known to block the binding of fibrogen to its receptor.
The one letter code RGD represents the amino acid sequence ______, which is known to block the binding of fibrogen to its receptor.
Blocking the binding site of fibrogen to its receptor prevents platelet ______, an action valuable in treating stroke and heart attacks.
Blocking the binding site of fibrogen to its receptor prevents platelet ______, an action valuable in treating stroke and heart attacks.
Somatostatin is a 14-residue peptide macrocyclized through a Cys-Cys ______ bridge.
Somatostatin is a 14-residue peptide macrocyclized through a Cys-Cys ______ bridge.
Thyrotropin-releasing hormone (TRH) derivatives show promise as leads for treating ______ disease and other cognitive disorders.
Thyrotropin-releasing hormone (TRH) derivatives show promise as leads for treating ______ disease and other cognitive disorders.
In pseudopeptides, modification to the peptide backbone via isosteric replacement, chain extension and amide ______ can improves drug-like qualities.
In pseudopeptides, modification to the peptide backbone via isosteric replacement, chain extension and amide ______ can improves drug-like qualities.
[Blank] and Rational Drug Design represent two major approaches in drug discovery, each with unique strengths and applications.
[Blank] and Rational Drug Design represent two major approaches in drug discovery, each with unique strengths and applications.
The binding pocket of HIV protease can be mapped by defining subsites such as $S1$, $S2$, $S3$, $S1\$, \$S2$ and $S3`$, useful for new peptedomimetic design, but what does the acronym HBA stand for in this context, i.e. which part of the molecule is it describing?
The binding pocket of HIV protease can be mapped by defining subsites such as $S1$, $S2$, $S3$, $S1\$, \$S2$ and $S3`$, useful for new peptedomimetic design, but what does the acronym HBA stand for in this context, i.e. which part of the molecule is it describing?
Many peptidomimetics can block platelet aggregation, which is valuable in the treatment of ______ and heart attacks.
Many peptidomimetics can block platelet aggregation, which is valuable in the treatment of ______ and heart attacks.
What class of proteases are responsible for peptide breakdown in the GI tract?
What class of proteases are responsible for peptide breakdown in the GI tract?
An advantage of using non-hydrolyzable peptidomimetics is that they may act as ______
An advantage of using non-hydrolyzable peptidomimetics is that they may act as ______
What is the name of the process when non-pharmacophoric polar sections of therapeutic peptides get replaced with lipophillic moieties?
What is the name of the process when non-pharmacophoric polar sections of therapeutic peptides get replaced with lipophillic moieties?
Briefly, summarise the function of glycoprotein IIb/IIIa.
Briefly, summarise the function of glycoprotein IIb/IIIa.
What type of amino acids leads to different conformational restriction profiles and differ in lipophilicity. The most common example is Phenylalanine.
What type of amino acids leads to different conformational restriction profiles and differ in lipophilicity. The most common example is Phenylalanine.
Why is solid phase organic synthesis important?
Why is solid phase organic synthesis important?
Flashcards
Oral Administration of Peptides
Oral Administration of Peptides
Enzymatic hydrolysis of peptide bonds in the gastrointestinal tract, kidney, and liver after oral administration.
Peptide Metabolism
Peptide Metabolism
Metabolism occurs in the lung, nasal mucosa, and blood after administration through other routes other than oral.
Key Metabolic Enzymes
Key Metabolic Enzymes
Key metabolic enzymes that cleave peptide bonds include carboxypeptidases, dipeptidyl carboxypeptidases, aminopeptidases, and amidases.
Hydrophilic Nature of Peptides
Hydrophilic Nature of Peptides
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Pepsin
Pepsin
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Trypsin
Trypsin
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Chymotrypsin
Chymotrypsin
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Decreasing Proteolysis
Decreasing Proteolysis
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Peptidomimetics
Peptidomimetics
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Non-Hydrolysable Peptide Mimic
Non-Hydrolysable Peptide Mimic
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Bioavailability
Bioavailability
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Phenylalanine Analogues
Phenylalanine Analogues
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RGD Sequence
RGD Sequence
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TRH Derivatives
TRH Derivatives
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Combinatorial Chemistry
Combinatorial Chemistry
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Rational design drug discovery
Rational design drug discovery
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Protease Function
Protease Function
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Common methods of Drug discovery
Common methods of Drug discovery
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Solid Phase Organic Synthesis
Solid Phase Organic Synthesis
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Protein Resistance
Protein Resistance
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Proteolysis Strategy
Proteolysis Strategy
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Nasal Delivery Enhancers
Nasal Delivery Enhancers
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Peptide Backbone Replacement
Peptide Backbone Replacement
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Structural Extension Benefits
Structural Extension Benefits
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RGD Mechanism
RGD Mechanism
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Somatostatin Structure
Somatostatin Structure
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Intact Peptide Drugs
Intact Peptide Drugs
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Transition State Mimicry
Transition State Mimicry
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HIV Protease Inhibitor Function
HIV Protease Inhibitor Function
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Trypsin, Chymotrypsin and Elastase
Trypsin, Chymotrypsin and Elastase
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Pharmacophore
Pharmacophore
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Somatostatin
Somatostatin
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HIV Protease Selectivity
HIV Protease Selectivity
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Protease Mechanism Key
Protease Mechanism Key
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Replacement Strategy
Replacement Strategy
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What is RGD?
What is RGD?
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Glucose Scaffold Analogue
Glucose Scaffold Analogue
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What is Leuprolide?
What is Leuprolide?
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Peptide modification.
Peptide modification.
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Combinatorial Approach
Combinatorial Approach
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D-Amino Acids Use
D-Amino Acids Use
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Lipophilic Modification
Lipophilic Modification
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Study Notes
- Peptides and proteins have issues as drugs due to enzymatic hydrolysis and poor passage through lipid membranes
- Metabolism of peptides occurs in the gastrointestinal tract, kidney, liver, lung, nasal mucosa, and blood
- Full-sized proteins have a compact globular nature, making them more resistant to breakdown than smaller peptides and polypeptides
- Key metabolic enzymes that break down peptides include carboxypeptidases (C-terminal residue cleavage), dipeptidyl carboxypeptidases, aminopeptidases (N-terminal cleavage), and amidases (internal cleavage)
- The stomach's gastric mucosa secretes pepsin
pH levels in digestion
- Stomach: pH ~2
- Small intestine: pH ~7
Enzymes
- Pepsin cleaves at carbonyl side of aromatic (Phe, Tyr & Trp) and acidic (Glu, Asp) residues
- Trypsin cleaves at carbonyl side of basic (Lys & Arg) residues
- Chymotrypsin cleaves at aromatic (Tyr, Phe, Trp) residues
- Elastase cleaves at small, sterically unhindered residues (Ala, Gly & Ser)
- Carboxy- and aminopeptidases further attack small units from the first wave of digestion
Decreasing Proteolysis
- Replacing L-amino acids with D-counterparts increases resistance to proteolysis
- This may increase resistance to proteolysis while retaining intended activity.
- Changing primary amide to secondary amides at key cleavage sites
- N-methylation or replacement of natural residue (wt) with proline is a common way to change a primary amide
- Other strategies include reversing the peptide bond or using pseudo peptides
- Co-administration of protease inhibitors and permeation enhancers aids in nasal delivery
Route Comparison Absorbed % Dose
- Oral: Insulin (0.05), Leuprolide (0.05)
- Nasal: Insulin (30), Leuprolide (2-3)
- Buccal: Insulin (0.5), Leuprolide (n/a)
- Rectal: Insulin (2.5), Leuprolide (8)
- Vaginal: Insulin (18), Leuprolide (38)
- Subcutaneous: Insulin (80), Leuprolide (65)
- Leuprolide is an analogue of gonadotropin-releasing hormone (GnRH)
Mimicking Peptides to use as Drugs
- Peptidomimetics mimic the structures of particular peptides
- Mimicry can fool a receptor into thinking it is binding the actual peptide
- A non-hydrolysable peptide mimic can act as a competitive inhibitor
- Replacing non-pharmacophoric polar sections with lipophilic moieties increases membrane permeation and bioavailability
- Most of the peptide backbone can be replaced with alternate atoms / groups
- Replacing phenylalanine analogues change conformational abilities and alter lipophilicity
- Structural extension can result in reinforcing interactions, resulting in higher affinity
RGD Scaffold Mimics
- RGD codes for the sequence arginine-glycine-aspartic acid
- It can block the binding of fibrinogen to its receptor, glycoprotein IIb/IIIa
- Blocking this binding prevents platelet aggregation
- Valuable in the treatment of stroke and heart attacks
Somatostatin
- Somatostatin (Growth Hormone Inhibiting Hormone) is a 14-residue peptide macrocyclised through a Cys-Cys disulphide bridge
- Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys
- A glucose scaffold analogue displays effective GH inhibition in cultured rat anterior pituitary cells
A peptidomimetic of thyrotropin-releasing hormone
- TRH: pyroGlu-His-ProNH2
- These compounds and their derivatives are leads for the treatment of Alzheimer's disease and other cognitive disorders
- Pseudopeptides are made using Isosteric replacement, Chain extension, and amide isosteres
Selected Drug Discovery Approaches
- Produce 100's → 1000's new compounds using Solid Phase Organic Synthesis (SPOS) in Combinatorial processes
- Used to test the level of activity against multiple targets using High Throughput Screening Assays
- Rational processes design drugs to fit receptor / active site (10 → 100 molecules)
- Rational is tested the final product against selected target(s)
HIV Protease Inhibitors
- HIV Protease Inhibitors are crucial for the formation of mature infectious virions
- They cleave viral polyproteins to produce functional viral proteins
- Proteases cleave amide bonds in other peptides
- HIV protease is selective for its peptide sequence
- Design with no cleavable peptide to mimic
Protease Mechanism
- Reaction uses a bound water molecule present in the active site
- Proceeds via a key diol intermediate
- Solid Phase Organic Synthesis is used widely in Combinatorial Chemistry
- Combinatorial Chemistry and Rational Drug Design are two major methods of drug discovery
- Clinical drugs can be developed from a detailed knowledge of the chemistry of a protein target
Saquinavir
- Saquinavir shows a sub nanomolar IC50 exhibiting a potent effect
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Description
Peptides and proteins face challenges as drugs because of enzymatic hydrolysis and poor absorption. Key metabolic enzymes like pepsin, trypsin, and chymotrypsin break down peptides, while proteolysis is decreased by replacing L-amino acids.
