The emerging technologies such as multifunctional peptides have greatly contributed to the prosperity of the peptide drug field. Here we introduce multifunctional peptides in detail.

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Multifunctional Peptides: Novel Direction of
Peptide Drug Development
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

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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.

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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

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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.

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

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Pegcetacoplan
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).

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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
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.
Conclusion
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.

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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.
References:
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). https://doi.org/10.1038/s41573-020-00135-8
3. Deshaies, R.J. Multispecific drugs herald a new era of biopharmaceutical
innovation. Nature 580, 329–338 (2020). https://doi.org/10.1038/s41586-020-2168-1
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