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Strategies to Optimize Peptide Stability and Prolong Half-Life

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Peptide Therapeutics

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 47))

Abstract

Peptide drugs represent 5% of the global pharmaceutical market, but growing twice as fast as the rest of the drug market. The development of peptide therapeutics is challenging due to their low stability, short half-life, and poor oral bioavailability. However, peptides typically have exquisite potency, selectivity, and low toxicity, making them particularly attractive for certain disease targets. Significant technological innovations have enabled the rapid advancement of peptide therapeutics to the clinic. Here, strategies to improve peptide proteolytic stability and prolong half-life are discussed. Structural modifications are highly effective for enhancing peptide stability, including replacing the natural L-amino acids with D- or unnatural amino acids, peptide backbone modifications, protecting N- and C-termini, and cyclization. In vitro and in vivo assays are available to assess peptide stability and develop structure-stability relationships to enable the design of more stable peptides. Peptides will continue to play an important role in filling the gaps between small molecule drugs and protein therapeutics.

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Abbreviations

ADA:

antidrug antibody

BBMV:

brush border membrane vesicles

CaV:

voltage-gated calcium channel

CNS:

central nervous system

CYP:

cytochrome P450

DPP-4:

dipeptidyl peptidase 4

EDTA:

ethylenediaminetetraacetic acid

Fa:

fraction absorbed

Fc:

fragment crystallizable

GI:

gastrointestinal

GIP:

glucose-dependent insulinotropic polypeptide

GLP-1:

glucagon-like-peptide-1

HIV:

human immunodeficiency virus

HPLC:

High-performance liquid chromatography

LC-MS:

liquid chromatography–mass spectrometry

MW:

molecular weight

PK/PD:

pharmacokinetics/pharmacodynamics

PMSF:

phenylmethylsulfonyl fluoride

SAR:

structure-activity relationship

SC:

subcutaneously

SGF:

simulated gastric fluid

SIF:

simulated intestinal fluid

T2DM:

type 2 diabetes mellitus

TMDD:

target-mediated drug disposition

UGT:

uridine 5′-diphospho-glucuronosyltransferase

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Authors and Affiliations

  1. Department of Chemistry, Stanford University, Stanford, CA, USA

    Sophia M. Shi

  2. Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT, USA

    Li Di

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Correspondence to Li Di .

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Editors and Affiliations

  1. School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, College of Pharmacy, Monroe, LA, USA

    Seetharama D. Jois

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Shi, S.M., Di, L. (2022). Strategies to Optimize Peptide Stability and Prolong Half-Life. In: Jois, S.D. (eds) Peptide Therapeutics. AAPS Advances in the Pharmaceutical Sciences Series, vol 47. Springer, Cham. https://doi.org/10.1007/978-3-031-04544-8_4

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