Prodrugs of Peptides and Proteins for Improved Formulation and Delivery

Oliyai, R

doi:10.1146/annurev.pharmtox.33.1.521

Cited by 7 publications

(10 citation statements)

References 28 publications

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“…2,3 Additionally, peptide therapeutics have been developed as pro-drug forms that can be activated by specific enzymes. 4 The potential application of stimuli-responsive conformational transformation of peptides triggered by specific biological environments, however, has not been generally considered for the development of peptide therapeutics possessing selective cytotoxicity. Therefore, we reasoned that the stimuli-responsive conformational transformation of peptides possessing a constrained structure into a biologically active form triggered by specific biological microenvironmental factors may provide an effective strategy for achieving the development of peptide therapeutics with a high degree of specificity.…”

Section: ■ Introductionmentioning

confidence: 99%

Stimuli-Responsive Conformational Transformation of Peptides for Tunable Cytotoxicity

Lee

et al. 2019

Bioconjugate Chem.

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The stimuli-responsive conformational transformation of peptides possessing a constrained form triggered by specific biological microenvironment would provide an effective strategy for the development of highly specific peptide therapeutics. Here, we developed a peptide containing a cytotoxic helical KLA sequence with therapeutic specificity through the use of stimuli-responsive conformational transformation. The KLA peptide is modified to form a cyclic structure to allow for constrained helicity that confers low cytotoxicity. The modified KLA peptide is electrostatically complexed to hyaluronic acid to facilitate enhanced endocytosis into the cancer cells. After endocytosis, the peptide is released from the complex into the cellular cytoplasm by hyaluronidases on the surface of the cellular membrane. Specific intracellular stimuli then trigger the release of the strain that suppresses peptide helicity, and the inherent helical conformation of the KLA peptide is restored. Therefore, the stimuli-responsive conformational transformation of a peptide from low to high helicity selectively induces cell death by disruption of the plasma and mitochondrial membrane.

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Section: ■ Introductionmentioning

confidence: 99%

Stimuli-Responsive Conformational Transformation of Peptides for Tunable Cytotoxicity

Lee

et al. 2019

Bioconjugate Chem.

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“…A prerequisite for success of the prodrug is the reliable conversion of prodrug to the parent drug through either enzymatic or non-enzymatic catalysed reaction, once the barrier to delivery has been circumvented. To preserve the physical and chemical integrity remains additional responsibility during prodrug fabrication for proteins [105,106]. There is plethora of examples where pro-drugs have been synthesized of proteins and have been studied for the stability and chemical reversibility at plasma after application.…”

Section: Prodrugmentioning

confidence: 99%

“…The use of monoclonal antibody-ricin A chain conjugates for selective delivery of this peptide toxin has also been studied. Similar scenarios can be envisaged where other prodrugs of polypeptides, including proteins, could be delivered conjugating it with membrane transporting carrier involving similar carrier-mediated mechanisms [106].…”

Section: Prodrugmentioning

confidence: 99%

Passive delivery of protein drugs through transdermal route

Chaulagain

Jain

Tiwari

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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Skin is the largest external organ in the human body but its use for therapeutic purposes has been minimal. Stratum corneum residing on the uppermost layer of the skin provides a tough barrier to transport the drugs across the skin. Very small group of drugs sharing Lipinski properties, i.e. drugs having molecular weight not larger than 500 Da, having high lipophilicity and optimum polarity are fortunate enough to be used on skin therapeutics. But, at a time where modern therapeutics is slowly shifting from use of small molecular drugs towards the use of macromolecular therapeutic agents such as peptides, proteins and nucleotides in origin, skin therapeutics need to be evolved accordingly to cater the delivery of these agents. Physical technologies like iontophoresis, laser ablation, micro-needles and ultrasound, etc. have been introduced to enhance skin permeability. But their success is limited due to their complex working mechanisms and involvement of certain irreversible skin damage in some or other way. This review therefore explores the delivery strategies for transport of mainly peptide and protein drugs that do not involve any injuries (non-invasive) to the skin termed as passive delivery techniques. Chemical enhancers, nanocarriers, certain biological peptides and miscellaneous approaches like prodrugs are also thoroughly reviewed for their applications in protein delivery.

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“…In our continuing effort to develop a novel GLP‐1 analogue, we designed and produced a polymer of GLP‐1 by polymeric prodrug strategy, termed Poly‐GLP‐1. Poly‐GLP‐1 consists of repeated bioactive GLP‐1 linked by linker peptide [17–21]. The polymer was produced in Escherichia coli as a single polypeptide chain containing 240 amino acids.…”

Section: Introductionmentioning

confidence: 99%