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Multifunctional Peptides: Novel Direction of Peptide Drug Development

Release time:2023/3/30 10:56:35

The emerging technologies such as multifunctional peptides, binding peptides, peptide conjugates, oral peptides, long-act…

Over nearly a century of development, peptide drugs have penetrated numerous disease areas, and are particularly prominent commercially and clinically in certain metabolic and rare diseases, possessing an irreplaceable position in three indications in particular: diabetes mellitus, acromegaly and postpartum hemorrhage.
Peptides are compounds formed when α-amino acids are linked together by peptide bonds
and generally have a molecular weight of 10 kDa or less. Generally, peptides composed of less than 10 amino acids are called oligopeptides, and peptides composed of 10-100 amino acids are called polypeptides.

Figure 1. Polypeptide Sequences. Credit: NIH.

In recent years, natural peptides have been enriched, especially peptidomics from venom and new chemical modification methods are advancing the discovery of novel peptide drugs. The emerging technologies such as multifunctional peptides, binding peptides, peptide conjugates, oral peptides, long-acting, and delivery systems have greatly contributed to the prosperity of the peptide drug field. In this paper, we introduce multifunctional peptides in detail.

For innovative peptide drug development, pharmaceutical scientists must go beyond traditional peptide technology, and "multifunctional peptide" with multiple pharmacological activities is one of the most representative areas of multi-specific drugs, and there are already bifunctional peptides and trifunctional peptides, of which Pegcetacoplan and Tirzepatide will be approved for marketing in 2021 and 2022, respectively.

Introduction to Multi-functional Peptides

Multifunctional peptides are peptide molecules that are coupled by two or more peptide sequences, which have multiple targets, multiple pharmacological activities, synergistic effect between different mechanisms and better safety. Multifunctional peptides are especially suitable for treating complex diseases, such as cardiovascular diseases, metabolic diseases, neurological diseases, and tumors.

The development of multifunctional peptides requires in-depth research based on genomic information and disease biology, where the simultaneous activation of different signaling mechanisms maximizes biological activity, minimizes side effects, and provides a more balanced pharmacokinetic action profile, providing patients with a full range of systemic and multi-target therapeutic options.

Combination Forms of Bifunctional Peptides

Multifunctional peptides can be classified into multifunctional fusion peptides, multifunctional linker peptides, multifunctional chimeric peptides, multifunctional stapled peptides, multifunctional cyclic peptides, and bicyclic peptides according to molecular types.

Figure. Structure of Multifunctional Peptide drugs

Linker Peptides

By introducing a linker to achieve the release of two ligands in their metabolism, interacting independently with each target.

Figure. Linker peptide example

For example, the above two opioid ligands are linked by a linker, which provides greater potency and selectivity compared to their monomers.

Fusion Peptides

As the size of the linker decreases until it can be directly conjugated, it is considered a "fusion".

Figure. Fusion peptides

For example, the above molecules, by adjusting the length of the carbon chain, end up in a compound with the best balance of activity at 8 carbon intervals. MT1013 and MT1009, which are already in the clinical stage, are fusion peptides.

Chimeric Peptides

Merging is achieved by exploiting commonalities in the structures of two target compounds.

Figure. Chimeric Peptides

For example, the above molecules, targeting the NK1/NK2 dual ligands for the same disease, are optimized to achieve a balance of activity based on structural commonalities. The most representative chimeric peptide is tirzepatide, which has just been approved for marketing.

Bicyclic Peptides

Bicycle Therapeutics has designed Bicycle using targeting peptides screened by phage screening platform. It is a short linear peptide forming two loops (composed of 9~15 amino acids) by the action of a scaffold with molecular weight of 1.5~2KDa, which has the advantages of good tissue permeability and renal clearance, high affinity and selectivity. And it is able to design more combination forms on this basis.

Figure. Bicyclic Peptides, source: Bicycle Therapeutics official website

Clinical Status of Multifunctional Peptides

In 2021, Apellis' bifunctional linker peptide Pegcetacoplan (APL-2) was approved for marketing, marking the beginning of the commercialization of multifunctional peptides. In 2022, Eli Lilly's bifunctional chimeric peptide Tirzepatide (LY3298176, TZP) was approved for marketing.

In addition to the 2 multifunctional peptides already on the market, more than 20 other drugs are in the clinical stage.


Pegcetacoplan (APL-2), co-developed by Apellis and Swedish Orphan Biovitrum, is a PEGylated cyclic peptide inhibitor of complement C3. The peptide portion of APL-2 binds to C3, exerting broad inhibition of the complement cascade and helping to prevent excessive complement activity.

Figure. Pegcetacoplan structure, source: Apellis official website

In 2021, the FDA approved Empaveli (pegcetacoplan) for the treatment of Paroxysmal nocturnal hemoglobinuria (PNH). Multicenter clinical trials have confirmed that Pegcetacoplan significantly improves hemoglobin levels in patients with PNH and is superior to Eculizumab in reducing patients' dependence on blood transfusions and relieving symptoms of fatigue. Most studies have combined Pegcetacoplan with Eculizumab to avoid the risk of hemolysis that may result from abrupt drug adjustments. Studies have shown a significant difference in 5-year survival between PNH patients treated with complement inhibitors and those who did not receive any complement inhibition (95.5% vs. 66.8%).

On February 17, 2023, the FDA approved Syfover (pegcetacoplan) injection for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

Pegcetacoplan is also currently involved in several additional clinical trials as potential treatments for other complement-mediated diseases involved in nephrology, ophthalmology, hematology, and neurology.


Tirzepatide is the first and currently the only FDA-approved GIP/GLP-1 dual receptor agonist. It integrates the actions of two incretins into a single molecule to achieve a dual glucose-dependent glucose-lowering effect once a week.

Figure. Tirzepatide structure. Source: https://doi.org/10.3390/molecules27134315

Tirzepatide demonstrated superiority in both blood glucose (A1C) and weight reduction compared to Novo Nordisk injectable semaglutide in the 40-week results of the type 2 diabetes head-to-head phase 3 SURPASS-2 clinical trial. Indications under investigation include obesity, cardiovascular risk-related disease, heart failure, and nonalcoholic steatohepatitis.

The FDA approval of Eli Lilly's Tirzepatide marks a golden era in the development of bifunctional peptide drugs. According to the analysis, Tirzepatide is expected to become another flagship product in the diabetes market after Dulaglutide, with analysts now expecting Tirzepatide sales to exceed $1 billion in 2023 and reach $17.5 billion by the end of 2030. Tirzepatide also ranked first in Evaluate Pharma's Top 10 Most Valuable R&D Projects by 2021 report with a net present value of $18.7 billion.


Bifunctional peptides are not simply merging target molecules from a framework, but require continuous design and optimization at the pharmacophore level. It requires rational modification of the molecular structure because the merging of different ligands often causes complications in the overall molecular structure.

It should be noted that for highly diverse targets, achieving multiple activities in a single compact molecule has proven to be impossible or undruggable. This is because it is much more difficult to adjust the ratio of activities against highly different targets, while the differences in relative metabolic rates between different disease severity and different patients lead to such candidates being rather inferior to monotherapeutic combinations, which are more flexible in terms of dosing depending on the actual situation.

Therefore bifunctionality is only easier to achieve and more effective when drugs are designed rationally to work synergistically against similar targets or different targets in the same indication.

Systematic discovery of bi/multifunctional peptides is a new field, full of opportunities and challenges.

Huateng Pharma is an innovative pharmaceutical company integrating R&D, manufacturing and sales of drug intermediates, mainly focusing on CMO/CDMO services for intermeiates of antiviral, antineoplastic, diabetic and hypertensive drugs.
Huateng Pharma, founded in 2013, is dedicated to R&D, production and sales of pharmaceutical intermediates related products. Huateng Pharma has an R&D center and a manufacturing base (4 production workshops). It has a step-by-step scale-up technology to meet the needs of different batches, from mg level to 50kg/batch.

1. Lau JL, Dunn MK. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg Med Chem. 2018;26(10):2700-2707. doi:10.1016/j.bmc.2017.06.052
2. Muttenthaler, M., King, G.F., Adams, D.J. et al. Trends in peptide drug discovery. Nat Rev Drug Discov 20, 309–325 (2021).
3. Deshaies, R.J. Multispecific drugs herald a new era of biopharmaceutical innovation. Nature 580, 329–338 (2020).

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