Peptide Therapeutics Current Status And Future Directions

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Peptide Therapeutics: Current Status And
Future Directions

Peptide drug development has made great progress in the last decade thanks to new
production, modification, and analytic technologies. Peptide is a class of compounds
formed by multiple amino acids connected by peptide bonds, usually consisting of 10-100
amino acid molecules, which are connected in the same way as proteins, with a relative
molecular weight less than 10000.

In recent years, with the development and maturity of peptide synthesis technology,
peptide drugs have become one of the hot spots in drug development, and they have
been widely used in the prevention, diagnosis and treatment of tumor, cardiovascular and
cerebrovascular diseases, hepatitis, diabetes, AIDS and other diseases with broad
development prospects due to their wide indications, high safety and remarkable efficacy.

Characteristics of Peptide Drugs

Therapeutic peptides commonly act as hormones, growth factors, neurotransmitters, ion
channel ligands, or anti-infective agents.

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Figure 1. Peptides versus small molecules and biologics. Comparison of advantages and
drawbacks between peptides and small molecules or biologics. Source: reference [1]

 ① Peptide drugs have high safety and high target affinity and are mainly cleared
by proteolytic degradation and renal filtration. Their hydrolysis products are amino acids,
so the toxicity of metabolites of peptide drugs is generally not considered.

 ② Peptide drugs tend to use endogenous peptides as templates, which usually
have high target affinity and small off-target risk.

 ③ Peptide drugs are 2 times more likely to be approved for marketing through
clinical trials than small molecule drugs, and the average R&D cycle is 0.7 years less. The
development of peptide drugs has also been extended to several disease therapeutic
areas, including anti-infection, anti-tumor, physiological regulation, pain, heart failure,
osteoporosis, diabetes, vaccines, etc. It can be expected that peptide drugs may replace
existing small molecule chemical drugs in the near future.

 ④ Compared with proteins, peptides are chemically synthesized with mature
technology, easy to separate from impurities or by-products, high purity, and easy to
introduce unnatural amino acids. In contrast, the quality, purity and yield of recombinant

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proteins are difficult to guarantee; recombinant proteins also cannot introduce unnatural
amino acids and cannot be amidated at the ends, as well as have long production cycles
and high costs. Peptides are generally less costly than protein and antibody-based drugs
and more costly than most small molecule drugs to synthesize.

 ⑤ Peptides are easily degraded and have a short half-life and high plasma
clearance. The biggest problem of peptides is that they are difficult to be taken
orally, mainly due to the ease of degradation and difficulty in crossing intestinal mucosa.
In addition, peptides are easily hydrolyzed by plasma proteolytic enzymes after entering
the blood, which has a short plasma half-life and plasma clearance, affecting the efficacy
and route of administration selection, and therefore do not produce drug accumulation
effects.

 ⑥ Peptide drugs may become immunogenic as the number of amino acid
composition increases.

Peptide drugs are still facing some challenges, such as problems in drug design and
high-throughput screening, manufacturing process and product purity, which lead to
substandard product quality or excessive cost and limit the development of peptide drugs.
Meanwhile, there is a need not only to discover new peptide drugs but also to find new
dosage forms and drug delivery systems so that peptide drugs can continue to maintain
stability and activity when they enter the body.

Peptide Drugs Market Size

Up to now, there are more than 80 peptide drugs in the global market, covering a
market of more than 30 billion US dollars, And more than 170 peptides are in active
clinical development, with many more in preclinical studies.

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Figure 2. Peptide drugs approved since 2000, with their targets and indications, source:
reference [1]

According to QYResearch statistics, the global peptide drug market scale was about
$15.2 billion in 2010 and reached $28.5 billion in 2018, with a CAGR of 8.17%. Compared
with the global pharmaceutical market of about USD 1.3 trillion in 2018, the peptide drug
market scale accounts for only 2.19%, and the growth rate of the peptide drug market
scale is about 2 times of the overall growth rate of the global drug market scale. It is
expected that the future peptide drug market will grow at a CAGR of 7.9%, reaching a
market size of $35.8 billion in 2021 and $49.5 billion in 2027.

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Figure 3. Global market size of peptide drugs

Among the marketed peptide drugs, there are several drugs with annual sales of over $1
billion, such as insulin, glatiramer acetate, liraglutide, dulaglutide, albiglutide, semaglutide,
teriparatide, abaloparatide, atrial natriuretic peptide, etelcalcetide, etc.

New Directions in Peptide Drug Development

In the past, when it comes to the innovation of peptide drugs, most of them are at the
formulation level, basically around the slow release technology such as microspheres, etc.
In fact, in recent years, many new technologies such as multifunctional peptides, peptide
drug conjugates (PDC), Cell-Penetrating Peptides, etc. have appeared in the field of
peptide innovative drugs, which provide strong technical support for the innovation of
peptides.

Multifunctional Peptides

Multifunctional peptides are the coupling of multiple peptide functional sites to perform
multiple functions and simultaneously improve the efficacy and druggability of indications.
The simultaneous activation of different signaling mechanisms maximizes bioactive
benefits, minimizes side effects, and provides a more balanced pharmacokinetic profile

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than that of a single peptide. Most of these studies are currently being developed by large
pharmaceutical companies, including Eli Lilly, Merck, Johnson & Johnson, Sanofi, Novo
Nordisk, and others.

Figure 4. Multifuncional Peptide Drugs in clinic trials

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Peptide Drug Conjugates (PDCs)

Peptide Drug Conjugates (PDC) are a new type of drug conjugates that couples a
cell-targeting peptide with a drug molecule to enhance drug targeting, improve
effectiveness and reduce adverse effects. Compared to antibody-drug conjugate (ADC), it
relies on a peptide chain of about 10 amino acids to target tumor cells, so it does not bring
about an immune response; it can be prepared on a large scale using solid-phase
synthesis; it can be rapidly eliminated by the kidney and is less toxic to the bone marrow
and liver. Unlike phages, adenoviruses, or other microorganisms used exclusively for
transporting drugs, this vector does not contain infectious substances.

Figure 5. Peptide drug conjugates mechanism of action

On February 26, 2021, Pepaxto (melphalan flufenamide, also known as melflufen), a
peptide-coupled drug developed by Oncopeptides, received accelerated approval for
marketing by the FDA in the U.S., becoming the second PDC drug on the market

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worldwide, triggering a wave of interest in PDC drugs. Unfortunately, in October 2021,
melphalan flufenamide was withdrawn from the US market. Internationally, more than
seven products have entered the clinic, and the companies with faster progress include
Oncopeptides, Bicycle Therapeutics, Cybrexa Therapeutics, Peptidream, etc.

Cell-Penetrating Peptides (CPPs)

Cell-penetrating peptides (CPPs) are a class of peptides consisting of usually no more
than 30 amino acid residues that can directly cross the cell membrane and enter the cell.
They are positively charged peptide fragments of varying lengths, rich in basic amino acid
residues such as arginine and lysine, and have an α-helical spatial conformation in their
secondary structures. Using these properties, more penetrating and efficient membrane
penetrating peptides PEp-1 and MPG have been synthesized and successfully carry
active substances (such as small molecule drugs, peptides, proteins, siRNAs, and
nanoparticles) into cells to exert biological activities, and some scholars call these short
peptides as protein transduction domains or Trojan horse peptides. Cell-penetrating
peptides can effectively promote transdermal absorption of biomolecular drugs, and are of
great value in targeted formulations, transdermal drug delivery formulations and cosmetic
fields, which can significantly improve the bioavailability of drugs.

Peptide vaccines

Peptide vaccines are vaccines prepared by chemical synthesis techniques following the
amino acid sequence of a known or predicted segment of an antigenic epitope in the
antigenic gene of a pathogen.

Tumor therapeutic peptide vaccines are one of the important directions. The difference
between tumor cells and normal cells can be described as many different, but the most
fundamental difference is due to the mutations of tumor cells. There are many tumor cells
with various mutations, and some of them are presented to the surface of tumor cells by
MHC, which are then specifically recognized by TCR of T cells, thus directly killing tumor

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cells, and such mutated peptides are called neoantigen. If neoantigens specific to tumor
cells can be identified and used as amino acid sequences to develop cancer vaccines,
they can activate relevant immune cells to kill tumor cells with the same antigen. Current
challenges include poor immunogenicity and efficacy limited by HLA phenotype.

Prophylactic peptide vaccines will be a much-needed emerging field. From inactivated
vaccines to recombinant protein vaccines to mRNA vaccines, immunodeficient
populations cannot be adequately protected, and a paper in the November 24, 2021 issue
of Nature gives us hope of closing the gap. A peptide COVID-19 vaccine called CoVac-1,
designed under the leadership of the University of Tübingen, Germany, has demonstrated
good safety, reactogenicity and immunogenicity in phase I clinical trials and good
protection against a variety of current mutant strains. Phase II clinical trials are currently
underway for this vaccine. The main active ingredients of this vaccine are specific T-cell
epitopes from a variety of covid-19 virus proteins (including spiked proteins, nucleoprotein
shells, membrane glycoproteins, envelope glycoproteins, etc.) that bind to the Toll-like
receptor agonist XS15 and are emulsified in adjuvant, allowing the vaccine to produce a
durable T-cell response.

Figure 6. Peptide vaccines

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Novel Delivery Systems

It is a very meaningful thing to upgrade the existing finished peptide drugs because of
their short half-life. The current ideas for the improvement of peptide drugs are generally
long-lasting injectable products, such as the preparation of peptide liposomes, peptide
microspheres, polyethylene glycol (PEG) modification, fusion proteins or subcutaneous
implantation, and secondly, bypassing injection, oral administration, transdermal
administration and inhalation administration.

PEG is a non-biodegradable, non-toxic, low-immunogenic polymer. PEGylation increases
the effective molecular weight of peptides to reduce their renal clearance through renal
filtration. PEG molecules can also protect peptides from protease digestion by increasing
steric hindrance and help increase absorption by increasing the water solubility of the
target peptide. These advantages have made PEGylation a common strategy for
modifying therapeutic peptides, and PEGylation has been used with great success since
the 1970s to optimize peptide therapy. Currently, there are more than 10 PEGylated
peptide therapeutics on the market, with many more potential candidates in clinical trials

High Throughput Screening Technology

Peptide Information Compression Technology (PICT) can dramatically reduce the cost of
peptide library construction and new drug screening, and improve the library construction
efficiency by 6000 times. Specifically, building a peptide library with this technology can
provide a valuable "seed library" containing nearly 500 million peptide information for
peptide drug discovery, solve the core technical bottleneck of discovering lead
compounds in global peptide drug discovery, significantly shorten the peptide drug
discovery cycle and reduce the R&D cost.

Peptides have become a unique class of therapeutic agents in recent years as a result of
their distinct biochemical characteristics and therapeutic potential. Biopharma PEG, as a
professional PEG supplier, offers PEGylation as a cost-effective modification of

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peptides which has the potential to improve bioavailability compared to the unmodified
molecule.

Reference:
[1] Wang, L., Wang, N., Zhang, W. et al. Therapeutic peptides: current applications and future
directions. Sig Transduct Target Ther 7, 48 (2022). https://doi.org/10.1038/s41392-022-00904-4

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