Therapeutic peptides: technological advances driving peptides into development

Sato, Aaron K.; Viswanathan, Malini; Kent, Rachel B.; Wood, Clive R.

doi:10.1016/j.copbio.2006.10.002

Cited by 318 publications

(233 citation statements)

References 42 publications

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“…In comparison with small drug molecules, peptides face some specific challenges (e.g. stability or short plasma half-lives) but also feature several benefits such as high selectivity and low toxicity (Sato et al 2006). In addition, peptidic drugs are more successful in inhibiting large protein-protein interactions, which are common in the complement cascade.…”

Section: Discovery and Initial Characterizationmentioning

confidence: 99%

“…Even though there are no clinical data available for compstatin so far, there are nevertheless many indicators from in vitro, ex vivo, and in vivo studies that constitute a high degree of drug-likeliness to the peptide. Degradation, metabolism, and rapid (renal) excretion are some of the recurrent challenges in the development of peptidic drugs, which often lead to short plasma half-lives (Sato et al 2006). In case of compstatin, the cyclic structure is largely responsible for a rather low degree of biotransformation in serum compared to previously investigated peptides for complement inhibition .…”

Section: From Bench To Bedside: Clinical Developmentmentioning

confidence: 99%

“…However, since the peptide is likely to be used in acute phase situations as well as local or extracorporeal applications, a short plasma half-live may not be as limiting as in the case of chronic, systemic administration. On the other hand, unfavorable pharmacokinetic properties could potentially be modulated by chemical modifications such as PEG-ylation (Sato et al 2006). …”

Section: From Bench To Bedside: Clinical Developmentmentioning

confidence: 99%

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Compstatin: A Complement Inhibitor on its Way to Clinical Application

Ricklin

Lambris²

2008

Advances in Experimental Medicine and Biology

116

166

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Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic. Tackling Complement at its CoreTherapeutic intervention in the human complement system has long been recognized as a promising strategy for the treatment of a series of ischemic, inflammatory and autoimmune diseases (Lambris and Holers 2000;Ricklin and Lambris 2007a). In principle, the large network of soluble and cell-surface-bound proteins, which builds the base of the complement cascade, offers a variety of potential drug targets. However, the quest for complement-specific therapeutics proved to be much more challenging than initially anticipated. With the therapeutic antibody eculizumab (Soliris ® , Alexion Pharmaceuticals, Inc.) against paroxysmal nocturnal hemoglobinuria, the first drug with proven complement connectivity has been marketed only recently (Ricklin and Lambris 2007a;Rother et al. 2007). A second complement-associated compound, purified C1 esterase inhibitor (C1-INH), is available as a therapeutic option for the treatment of hereditary angioedema in several countries. However, its mechanism of action may be closer related to the bradykinin-kallikrein than the complement cascade (Davis 2006). Strikingly, both drugs cover relatively rare diseases and have been developed with the aid of orphan drug regulations. Yet, for many of the more common inflammatory or autoimmune conditions there are no complement drugs on the market. Any extension of the current complement-specific therapeutic arsenal is therefore highly desired.Part of the problem in complement-directed drug discovery is the selection of the right target (Ricklin and Lambris 2007a activation is considered to be the most promising approach in many cases. On a molecular level, inhibition at the level of C3, including the C3 convertases, is of particular interest since both the amplification of all initiation pathways and the generatio...

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Section: Discovery and Initial Characterizationmentioning

confidence: 99%

Section: From Bench To Bedside: Clinical Developmentmentioning

confidence: 99%

Section: From Bench To Bedside: Clinical Developmentmentioning

confidence: 99%

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Compstatin: A Complement Inhibitor on its Way to Clinical Application

Ricklin

Lambris²

2008

Advances in Experimental Medicine and Biology

116

166

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“…Peptides are short polymers of amino acids that are generally less than 50 units long with a molecular weight of less than 10 kDa (7,8). Peptides have unique therapeutic advantages compared to larger biologics including a higher activity per unit mass, better tissue penetration, decreased potential for immunogenicity, and lower manufacturing costs when comparing solid phase peptide chemistry to the traditional recombinant protein expression methodologies required for larger protein therapeutics.…”

Section: How Do We Define a Peptide?mentioning

confidence: 99%

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

Furman

Chiu

Hunter

2014

AAPS J

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Abstract. Downstream success in Pharmaceutical Development requires thoughtful molecule design early in the lifetime of any potential therapeutic. Most therapeutic monoclonal antibodies are quite similar with respect to their developability properties. However, the properties of therapeutic peptides tend to be as diverse as the molecules themselves. Analysis of the primary sequence reveals sites of potential adverse posttranslational modifications including asparagine deamidation, aspartic acid isomerization, methionine, tryptophan, and cysteine oxidation and, potentially, chemical and proteolytic degradation liabilities that can impact the developability and manufacturability of a potential therapeutic peptide. Assessing these liabilities, both biophysically and functionally, early in a molecule's lifetime can drive a more effective path forward in the drug discovery process. In addition to these potential liabilities, more complex peptides that contain multiple disulfide bonds can pose particular challenges with respect to production and manufacturability. Approaches to reducing the disulfide bond complexity of these peptides are often explored with mixed success. Proteolytic degradation is a major contributor to decreased half-life and efficacy. Addressing this aspect of peptide stability early in the discovery process increases downstream success. We will address aspects of peptide sequence analysis, molecule complexity, developability analysis, and manufacturing routes that drive the decision making processes during peptide therapeutic development.

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“…Notably, small peptides (< 5 kDa) are rapidly degraded and thus can have extremely short half-lives. 21) In this regard, fusion peptide can enhance its stability. In this study, deoxyoligonucleotide encoding grass carp PACAP 38 was designed according to the codon preference of E. coli, which improved the translation efficiency of grass carp PACAP in the E. coli expression system.…”

mentioning

confidence: 99%

High-Level Expression, Purification, and Characterization of the Recombinant Grass Carp Pituitary Adenylate Cyclase-Activating Polypeptide

Wang

et al. 2008

Bioscience, Biotechnology, and Biochemistry

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Therapeutic peptides: technological advances driving peptides into development

Cited by 318 publications

References 42 publications

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Early Engineering Approaches to Improve Peptide Developability and Manufacturability

High-Level Expression, Purification, and Characterization of the Recombinant Grass Carp Pituitary Adenylate Cyclase-Activating Polypeptide

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