Peptidomimetics in Modern Drug Discovery

Expert-driven In Silico Drug Discovery Solutions
15 September 2021
Andrew Golub
Group Leader, Molecular Design

Many important physiological activities in the human body are controlled by peptides, including immune defense, digestion, metabolism, reproduction, breathing, and sensitivity to pain [1]. Along with good efficacy and tolerance, peptides exhibit favorable characteristics in the development stage, such as predictable metabolisms, short time to market and low attrition rates. Increasingly, peptides are entering clinical trials, being then approved as drugs owing to advances in structural optimization, formulation and production [1,2]. At the same time, these molecules have several disadvantages, such as:

  1. Limited stability towards proteolysis, resulting in a half-time in the order of minutes in the gastrointestinal tract and serum;
  2. High molecular mass and lack of specific transport systems that lead to poor absorption and transport properties, often causing rapid excretion through the liver and kidneys;
  3. Because of the intrinsic flexibility of N–Cα and Cα–CO rotational bonds in each amino acid, peptides can interact with multiple targets, which leads to poor selectivity and unwanted side effects;
  4. Peptides can induce an immune response in a competent host due to the interaction with binding sites of antibodies [3].

Peptidomimetics are synthetic molecules created to mimic natural peptides in three-dimensional form so that they retain the same biological activity while reducing the risks of their natural counterparts, including stability, proteolysis resistance, and bioavailability (Fig. 1). Such structurally modified peptide drugs are intended to disrupt the large and flat interfaces of their respective biological targets. Thus, peptidomimetics are developed to overcome the limitations listed above because they possess good metabolic stability, good bioavailability, and high receptor affinity and selectivity. Their general design implies the lead peptide structure optimization by adding functional modifications that can overcome intrinsic peptide disadvantages while maintaining the structural features responsible for its biological activity [4]. In modern medicinal chemistry and drug discovery, the art of converting peptides into drug candidates is a dynamic and fertile field. To modulate the conformational flexibility and the peptide character of peptidomimetic compounds, so far various synthetic strategies have been developed.

Advantages of peptidomimetics over peptides.


Fig. 1. Advantages of peptidomimetics over peptides. Source: Chem. Soc. Rev., 2020, 49, 3262-3277.

The classification of peptidomimetic compounds has changed over time, from a historical arrangement based on structural and functional characteristics into a more comprehensive one incorporating new approaches based on foldamers and peptoids with high molecular weights. Historically, the peptidomimetics were classified according to their similarity to their native substrate [5]: 

  1. The mimetics of Type I, or structural mimetics, exhibit a strict analogy to the substrate since they carry all its functions within the same spatial orientation; 
  2. Functional mimetics, also known as Type II mimetics, do not exhibit apparent structural analogies with the native substrate but are still able to mimic its function by interacting similarly with receptors or enzymes;
  3. Type III mimetics, or functional-structural mimetics, represent interacting elements in the same spatial orientation as the native substrate while having a significantly different scaffold. 

The new classification, recently proposed by Grossmann and coworkers [6], classifies peptidomimetics based on their degree of peptide character: 

  1. Mimetics of Class A are most similar to its parent peptide since only a limited number of changes are introduced to stabilize their conformation and reduce the probability of proteolysis degradation;
  2. The backbone and side chains of Class B mimetics are still peptide-like, but they contain more significant structural modifications. In addition, they might include various amino acids that are not naturally occurring, small molecule building blocks, and backbone mimetics; 
  3. Class C mimetics are characterized by a pronounced small-molecule structure, in which the backbone is entirely replaced by a nonpeptide unnatural framework ; 
  4. As compared to their parent peptides, Class D mimetics resemble them the least. They are either designed with a hit-to-lead process, which starts with Class C mimetics, or generated as a result of compound libraries screening.

Today, nearly a century after the introduction of insulin, more than 80 peptide drugs have reached the market for a wide variety of illnesses, including diabetes, cancer, osteoporosis, multiple sclerosis, AIDS, and chronic pain (Fig. 2, 3). In addition to human endogenous peptides, peptide drug discovery has expanded to include a wider range of natural sources and compounds identified through medicinal chemistry. Around 200 peptides are in active development nowadays, which represents an efficient toolbox for therapeutic use.

Historical timeline of key milestones, developments and drug approvals in the peptide therapeutics field

 Fig. 2. Historical timeline of key milestones, developments and drug approvals in the peptide therapeutics field. Source: Muttenthaler, M., King, G.F., Adams, D.J. et al. Trends in peptide drug discovery. Nat Rev Drug Discov 20, 309–325 (2021).

Molecular targets of peptides entering clinical development.

Fig. 3. Molecular targets of peptides entering clinical development. Source: Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorganic & Medicinal Chemistry. 2018, 26(10), 2700-2707.

If your area of research involves peptides and peptidomimetics, please take a moment to explore a list of Life Chemicals products and services related to peptide/peptidomimetics drug discovery:

Please, contact us at orders@lifechemicals.comfor any details and quotations.

Welcome to visit our Website for more information and download SD files with compound structures in the Downloads section. Custom compound selection based on specific parameters can be performed on request, with competitive pricing and the most convenient terms provided.


  1. K. Fosgerau and T. Hoffmann, Drug Discovery Today, 2015, 20, 122–128.
  2. N. Qvit, S. J. S. Rubin, T. J. Urban, D. Mochly-Rosen and E. R. Gross, Drug Discovery Today, 2017, 22, 454–462.
  3. M. H. Van Regenmortel, Biologicals, 2001, 29, 209–213.
  4. A. Trabocchi and A. Guarna, Peptidomimetics in Organic and Medicinal Chemistry: The Art of Transforming Peptides in Drugs, John Wiley & Sons Ltd, Chichester, UK, 2014
  5. A. S. Ripka and D. H. Rich, Curr. Opin. Chem. Biol., 1998, 2, 441–452.
  6. M. Pelay-Gimeno, A. Glas, O. Koch and T. N. Grossmann, Angew. Chem., Int. Ed., 2015, 54, 8896–8927.
15 September 2021, 16:41 Andrew Golub Computational Chemistry

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