Peptides consist of polyamide main chains bearing substituents. ¹ There are around 7000 known naturally occurring peptides, and these peptides have a wide range of biological functions, including those of hormones, immunomodulators, substrates, enzyme inhibitors, and neurotransmitters. 2 After binding to their corresponding receptors or enzymes, they can influence cell-cell communication and control a series of vital functions such as metabolism, immune defense, digestion, respiration, sensitivity to pain, reproduction, behavior, and electrolyte levels. In order to build new peptide-based medicinal medicines, a great deal of research has been done to try to understand the physiological consequences of these peptidic molecules. ³

The use of peptides as therapeutic agent is significantly limited by several factors: a) due to the high molecular weight and pronounced polarity peptides are poorly absorbed after oral administration. B) peptides are metabolically unstable because they easily degraded by proteases in the gastrointestinal tract and in serum. c] peptide quickly excrete via the liver and kidneys. d] their side-effects caused by interaction between conformationally flexible peptides with distinct receptors. ^{4, 5}

Peptidomimetic drug design has become a crucial technique for medicinal chemists and peptide chemists alike in an attempt to address these issues. ⁶ This approach has evolved as an interdisciplinary scientific endeavor combining organic chemistry, biochemistry and pharmacology. ⁷ The term “peptidomimetics” ⁸ can encompass compounds designed to resemble peptide main chains, side chains, or both. ^{9, 10} Peptidomimetics that can present side chains on main-chain scaffolds containing amide bonds are ubiquitous because medicinal chemists frequently design analogues of bioactive peptides using this approach. ¹¹ For instance, peptidomimetics involving substitution of amide bonds with surrogate or transition-state analogues are common. compounds that mimic secondary structures by peptide modifications. ¹² Since the term originated in the late 1970s, peptididomimetics are synthetically modified peptides with modified molecular properties for particular biological or therapeutic applications have been a significant class of drug molecules because of their potential features, high potency, and low toxicity. ¹³

A number of compounds have been created to imitate the secondary structures of peptides, including helices, P-turns, and P-sheets, as part of one of the main initiatives in organic chemistry. ¹⁴ In order to explore the structure-activity relationships (SAR) of bioactive peptides, a number of strategies have been developed by incorporation of conformationally constrained amino acids, modification of the peptide backbone by amide bond isosteres, cyclization’s, attachment of pharmacophores to a template or scaffold, and the synthesis of nonpeptide analogs. Due to these efforts, it has been shown that peptidomimetics are superior to native peptides in terms of potency and selectivity, adverse effect reduction, oral bioavailability, and half-life of activity due to reduced enzymatic degradation. ^{15, 16} Using peptidomimetics is one approach to get overcome these drawbacks of natural short polypeptides. These tiny molecules mimic proteins and are made by mimicking natural peptides or proteins. ¹⁷ These mimetics should have the ability to bind to their natural targets in the same way as the natural peptide sequences do from which their structure was derived and hence should produce the same biological effects. ¹⁸ These compounds can be synthesized to exhibit the same biological effects as their peptide analogs, but with improved characteristics such as increased bioavailability, increased proteolytic stability, and frequently increased potency or selectivity. They are therefore desirable targets for the development of novel therapeutic candidates. ¹⁹ Overall, the development of peptidomimetics is primarily based on understanding the electronic, conformational, and topochemical properties of the native peptide to its target. Two structural factors are particularly important for the synthesis of peptidomimetics with high biological activity: first, the mimetic must fit the binding site conveniently, and second, the functional groups, polar, and hydrophobic regions of the mimetic must be positioned in specific ways to enable the beneficial interactions to occur.

This article reviews the current development of peptidomimetics, the new classification is categories on the basis of their degree of similarity to the natural peptide precursor which is recently proposed by Grossmann and coworkers, discovery and development of peptidomimetics, strategies for the synthesis of peptidomimetic, pharmacological activity of modified peptide, challenges, limitation and future prospective of peptidomimetics.

Historically peptidomimetics categories on the basis of their similarity with the native substrate, but this classification of peptidomimetics does not comply with recent advancement in the field of chemistry and biotechnology. ^{20, 21, 22}

i. Type I (Backbone Modifications): These peptidomimetics focus on modifying the peptide backbone to mimic the local topography of the amide bond, often to enhance stability or prevent proteolysis.

ii. Type II (Functional Mimetics): These compounds mimic the biological activity of a peptide without necessarily mimicking its structure, focusing on binding to the same target site.

iii. Type III (Topographical Mimics): These peptidomimetics utilize novel scaffolds to position the relevant amino acid side chains, mimicking the overall shape and function of the parent peptide.

iv. Type IV (Non-peptide mimetics): These are structurally similar to type I peptidomimetics but bind an enzyme form that cannot be accessed by type I.

The new classification is categories on the basis of their degree of similarity to the natural peptide precursor which is recently proposed by Grossmann and coworkers. ^{23, 24, 25, 26, 27}

i. Class A (modified peptides): These primarily comprise the amino acid sequence of the parent peptide. To stabilize the bioactive conformation and lower the rate of proteolysis breakdown, just a small amount of modified amino acids is added. A class A mimetic's side chains and backbone closely match the precursor peptide's bioactive conformation.

ii. Class B (Foldamers): It contain additional modifications to class A mimetics that include significant backbone changes, isolated small-molecule building blocks, and/or different non-natural amino acids. Foldamers, such β- and α/β-peptides, and peptides that arrange their side chains topologically similarly to the precursor peptide are also included in this family.

iii. Class C (Structural mimetics): The peptide backbone is entirely replaced by significantly modified structures with small-molecule characteristics. Similar to how important residues (like hot spots) are oriented in the parent peptide's bioactive conformation, the central scaffold projects substituents.

iv. Class D (Mechanistic mimetics): These are compounds that, without having a direct connection to the side chain functions of a bioactive peptide, replicate its mode of action. These compounds can be produced by optimizing the affinity of a class C molecule, or they can be found through screening of compound libraries or virtual libraries in silico.

The history of mimicking peptides, or peptidomimetics, spans from the early 20th-century synthesis of peptides to their current use in drug discovery and biomaterials, with key milestones including the isolation of insulin and the development of strategies to stabilize and enhance peptide activity. ²⁸

German chemist Emil Fischer, a Nobel laureate, discovered the chemical reaction to join amino acids into a chain, creating peptides. ^{29, 30} The isolation of insulin from livestock pancreata in the 1920s and its use to treat diabetes marked a significant early application of peptides as therapeutics. 31 The development of peptide synthesis techniques, including solid-phase peptide synthesis, allowed for the creation of a wider range of peptides with diverse structures and functions. ³² Peptide hormones, their analogs, and mimetics became important in the pharmaceutical industry for hormonal replacement therapy and other applications. ³³ Peptidomimetic approaches have been used to design small molecules that selectively target cancer cells, an approach known as targeted chemotherapy. Peptides are also used in biomaterial engineering due to their biocompatibility, biodegradability, and functional selectivity. Researchers have focused on designing peptides that mimic specific protein-protein interactions, including those involved in disease processes. ^{34, 35}

Figure 4

The design and synthesis of these peptide-mimicking molecules require innovative strategies that often involve modifications to the peptide backbone, alteration of amino acid side chains, or the construction of entirely non-peptidic scaffolds.

The new period of peptide medicines comes with some bright news but also accompanied with being and implicit challenges. Some of the challenges have been addressed in the history as bandied in the below section, but other obstacles still need farther examinations. In this section, many of these challenges have been assessed completely. 68, 69, 70

Peptidomimetics offer a promising future in drug discovery and development. Here are some key prospective areas: 71, 72, 73

Peptidomimetics represent a promising frontier in modern drug discovery, offering significant advantages over native peptides, including enhanced metabolic stability, improved bioavailability, and increased target specificity. Through strategic modifications of the peptide backbone, incorporation of non-natural amino acids, and innovative structural scaffolding, peptidomimetics have demonstrated broad therapeutic potential across diverse areas such as oncology, infectious diseases, and immunomodulation. Although several challenges persist such as synthetic complexity, limited oral bioavailability, and potential immunogenicity ongoing advancements in molecular modeling, combinatorial chemistry, and high-throughput screening are facilitating the rational design of next-generation peptidomimetics. With continued interdisciplinary research, peptidomimetics are poised to play a pivotal role in the development of novel, efficacious, and safer therapeutic agents.