In 2023, the U.S. Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) hit a significant milestone, approving 55 new drugs, an increase of nearly 50% from last year and second only to the all-time high of 2018 . This number highlights the innovative trend in the pharmaceutical field and demonstrates the industry’s great success in different treatment areas. What is particularly eye-catching is that among the new drugs approved by the FDA in 2023, antibody drugs occupy a prominent position, including China’s domestic PD-1 monoclonal antibodies, which brings new hope to the medical community.

Among these 55 new drugs, oncology once again became the most approved treatment area, fully reflecting the medical community’s in-depth research on cancer treatment. At the same time, the fields of neurology and infectious diseases have also been recognized by the FDA, providing more treatment options for patients. The emergence of new drugs will promote the rapid development of medical technology and further promote progress in the health field.

It is worth mentioning that 2023 has also become a year of significant progress in the field of rare diseases, providing patients with new treatment options. Pfizer performed well this year. Not only did it become the company with the most approvals, it also launched a number of highly anticipated new products, covering multiple disease fields such as tumors, immunity, infection, and the nervous system.

In this dynamic year of medical innovation, it is worth noting that there are 6 new drugs that belong to the peptide drug category. They are:

1.Daybue (Trofinetide, Trofinetide)

• Developer: Acadia Pharmaceuticals
• Approval time: 2023-03-10
• Indications: Rett syndrome
• Delivery method: Oral solution (200 mg/ml), specific dosage is based on body weight
• Introduction: It is used to treat Rett syndrome and is the first approved therapy for Rett syndrome. It exerts neuroprotective effects by enhancing synaptic activity and restoring synaptic structure.

2.Rezzayo (Rezafungin, Rezafungin)

• Developer: Melinta Therapeutics/Cidara Therapeutics
• Approval time: 2023-03-22
• Indications: Candidemia and invasive candidiasis
• Delivery method: Intravenous injection (200 mg once weekly)
• Introduction: For the treatment of candidemia and invasive candidiasis, it is the first new treatment option approved for this indication in more than a decade.

3.Paxlovid (nirmatrelvir&ritonavir)

• Developer: Pfizer
• Approval time: 2023-05-25
• Indications: Covid-19
• Mode of delivery: Oral
• Introduction: It is used to treat COVID-19 and reduce the severity of the disease by preventing the virus from multiplying. It contains two peptidomimetic molecules, nirmatrelvir and ritonavir.

4.Posluma (flotufolastat F 18)

• Developer: Blue Earth Diagnostics
• Approval time: 2023-05-25
• Indications: Positron emission tomography imaging in patients with prostate cancer
• Delivery method: Intravenous injection
• Introduction: Positron emission tomography imaging for prostate cancer patients using PSMA targeting components for imaging.

5.Aphexda (Motixafortide, motixafortide)

• Developer: BioLineRx
• Approval time: 2023-09-08
• Indications: Collection and subsequent autologous transplantation in patients with multiple myeloma
• Delivery method: Subcutaneous injection
• Introduction: For the collection and subsequent autologous transplantation of patients with multiple myeloma, stem cells are mobilized into the peripheral blood by CXCR4 antagonists.

6.Zilbrysq(Zilucoplan)

• Developer: UCB
• Approval time: 2023-10-17
• Indications: Generalized myasthenia gravis in adults
• Delivery method: Subcutaneous injection
• Introduction: It is the first once-daily subcutaneous injection of gMG-targeted C5 complement inhibitor for the treatment of generalized myasthenia gravis in adults.

The approval of new drugs this year witnessed the joint efforts of medical research and industrial development, providing patients with more innovative treatments and writing a new chapter for building a healthier future.

In contrast to proteins and small molecules, peptides represent a unique class of pharmaceutical compounds that are biochemically and therapeutically distinct from both. As intrinsic signaling molecules for many physiological functions, peptides offer an opportunity for therapeutic intervention that closely mimics natural pathways. In recent years, peptides have received increasing attention as a therapeutic approach.

The origin and development of in vitro peptide drugs

Polypeptides are amino acid derivative compounds containing at least one amide (peptide) bond. From a structural point of view, polypeptides include various types of peptides, such as linear peptides, cyclic peptides, delipidated peptides, etc. According to function, they can also be divided into antibacterial peptides and hormones. Regulatory peptides, neuroactive peptides, etc. [1].

In the early 20th century, research on peptides focused primarily on the effects of human signaling hormones. Insulin is a classic example of endogenous hormone therapy. It was the first peptide drug to be used clinically and is by far the most commercially successful [2] because it revolutionized the treatment of type I diabetes.

Despite the success of early hormone analogs, the production of longer peptides was limited by synthetic methods. Therefore, selective expression of endogenous human peptides and proteins in cell culture systems is highly desirable, and the emergence of recombinant technology is a milestone in the development of peptide drugs. In 1982, the first recombinantly produced human peptide, somatostatin, was produced. Subsequently, the booming genetic engineering has realized the adjustment of individual amino acids to improve the absorption, distribution, metabolism and excretion characteristics of peptides in the body. Display technologies such as phage display, as well as new chemical methods are also driving the development of this field [2].

Figure 1. Development timeline of peptide drugs[2]

Advantages, disadvantages and new attempts of peptide drugs

The key factors for the success of peptide drugs are the effectiveness, specificity and safety of the mode of action of the peptide [3]. The rapid clearance of peptides from the body means that they do not accumulate in tissues and are relatively less toxic to the human body [4]. However, the limitations of peptide drugs are as obvious as their advantages. ​

Since peptide drugs are easily cleared from the serum, this also results in low bioavailability of peptide drugs. Furthermore, peptides generally have poor cell membrane permeability, which limits their use in targeting intracellular targets. Therefore, the development of peptide therapeutics has mainly focused on extracellular targets. Moreover, because they cannot penetrate the intestinal mucosa and need to be administered subcutaneously or intravenously, the convenience and compliance of peptide drugs in actual treatment are reduced [4].

Improving the bioavailability and efficacy of peptide drugs is also a popular research area. There have also been advances in universal and reproducible oral administration, as well as intracellular delivery of peptide drugs [4]. Cyclic peptides, a category of peptide drugs, are an emerging form of drugs designed to solve problems.

Cyclotides—a new form of peptide drugs

Cyclic peptides (including cyclodeposition peptides and bicyclic peptides) have many favorable properties as therapeutic agents and research tools. Compared with linear peptides, cyclic peptides have better proteolytic resistance and structural stability.

First, cyclization of peptides reduces the conformational freedom, greatly enhancing their metabolic stability and binding affinity/specificity to target molecules. In general, cyclic peptides with smaller ring sizes (10 aa) are relatively resistant to proteolytic degradation. Second, medium-sized cyclic peptides (6-15 aa; most commonly used MW = 500-2000 Da) are usually 3-5 times larger than traditional small molecule drugs (MW 500) and can form more complex molecules with target proteins. Large surface area. Therefore, cyclic peptides have the ability to reproduce exceptional protein affinity and specificity, even for targets without any binding pocket. Third, cyclic peptides exhibit enormous structural diversity. Using only these 20 protein-derived amino acids, 208 different cyclic peptides can be generated. And its structural diversity can be further increased by adding non-protein source amino acids. Fourth, compared with proteins, cyclic peptides retain some properties of small molecules, such as stability, lower risk of immune response, synthesizability, and lower production costs [5].

Figure 2. Angiotensin (1-7) is a heptapeptide that plays a key role in the renal angiotensin system, but its extremely short half-life limits its therapeutic potential. Moll uses a variant of Lactococcus lactis that produces the cyclic peptide Lanthipeptide A, which in rat studies showed an approximately 30-fold longer plasma half-life than Angiotensin (1-7) [4].

Currently, several cyclic peptides have become highly successful drugs, including vancomycin (antibacterial), daptomycin (antibacterial), cyclosporine A (transplantation immunosuppressant), and caspofenside (antifungal). Inspired by natural products, chemists have developed many methods to prepare cyclic peptides via N-to-C, side chain to side chain, or main chain to side chain cyclization. Some synthetic cyclic peptides, such as eptifibatide (used to treat heart disease), octreotide (a somatostatin mimetic used to treat acromegaly and diarrhea), cyclic RGD peptide, and linalotide Peptides have also been approved by the FDA for clinical or late-stage clinical trials [5].

Peptidomimetics – chemically synthesized peptide drugs

In terms of new drug strategies, in order to overcome the instability defects of peptides, in addition to modifying polypeptides to varying degrees like cyclic peptides, peptidomimetic compounds are also another reasonable means.

Peptidomimetic compounds are a class of compounds whose pharmacophore simulates natural peptides or proteins in three-dimensional space and retains the ability to interact with biological targets and produce the same biological effects [6]. The difference is that peptoids avoid the inherent defects of natural polypeptides and improve biological activity and stability.

Many non-peptide mimetics of bioactive peptides have been reported in the literature. αvβ3-integrin inhibitor SB223245 (Figure 3-1), γ-turn analog scaffold centered on 1-4 benzodiazepines, TRH (pGlu-His-Pro-NH2) analog (Figure 3-2), Contains a cis-1,3,5-trisubstituted cyclohexane scaffold, a glucose-derived non-peptide mimetic somatostatin (Figure 3-3), and c2 symmetric cyclic urea as an HIV protease inhibitor (Figure 3-4), These are outstanding examples of non-peptide peptidomimetics with high biological activity and increased enzyme stability [1].

Figure 3. Chemical formulas of some peptidomimetics[1]
(1) SB223245; (2) TRH (pGlu-His-Pro-NH2) analog; (3) Glucose-derived non-peptide mimetic somatostatin; (4) c2 symmetric cyclic urea

Table 1. Classic peptide drugs and their target

Peptide drugs, whether isolated from the innate immunity of various species (including mammals, amphibians, fish, insects, plants and bacteria), or designed based on structure-activity relationship research, serve as a new structural drug , all have great potential [7]. Here we introduce a high-throughput method that can quickly identify and find suitable drugs – constructing a peptide library.

The construction and use of peptide libraries generally involves gathering all the required peptides, uniformly culturing the samples, and then conducting high-throughput detection at the cellular or molecular level. For example, B. Guixer et al. determined the N-terminal and C-terminal forms by selecting the amino acids with specific functions they needed, and used the mixing-splitting method to synthesize a peptide library composed of different arrangements of the selected amino acids. Then, they conducted experiments simulating the blood-brain barrier to screen peptides that could pass through the peptide library, and finally obtained peptides (shuttle peptides) that had the ability to cross the in vitro blood-brain barrier model (Figure 4)[8].

Figure 4. Overall scheme of mass spectrometry-based high-throughput screening method[8]
(1) Library synthesis using the mixed fraction method on SPPS (solid-phase polypeptide synthesis); (2) Library analysis in an in vitro cell-based blood-brain barrier model; (3) Peptide identification using mass spectrometry technology to monitor specific amino acid sequences transformation.

Currently, there are nearly a hundred peptide drugs on the global market, and research on new peptide therapeutic drugs continues at a steady pace, with more than 100 peptides in the clinical development stage and another 400-600 peptides in the preclinical research stage [2 ]. The utilization of peptides as therapeutics has evolved over time and continues to evolve as drug development and treatment paradigms change.

references

1. Luca Gentilucci. Chemical modifications designed to improve peptide stability: incorporation of non-natural amino acids, pseudo-peptide bonds, and cyclization. Curr Pharm Des. 2010;16(28):3185-203.
2. Markus Muttenthaler. Trends in peptide drug discovery. Nat Rev Drug Discov. 2021 Apr;20(4):309-325.
3. Keld Fosgerau. Peptide therapeutics: current status and future directions. Drug Discov Today. 2015 Jan;20(1):122-8.
4. Antoine Henninot. The Current State of Peptide Drug Discovery: Back to the Future?. J Med Chem. 2018 Feb 22;61(4):1382-1414.
5. Patrick G Dougherty. Understanding Cell Penetration of Cyclic Peptides. Chem Rev. 2019 Sep 11;119(17):10241-10287. Epub 2019 May 14.
6. Josef Vagner. Peptidomimetics, a synthetic tool of drug discovery. Curr Opin Chem Biol. 2008 Jun; 12(3): 292–296.
7. Sylvie E Blondelle. Optimization and high-throughput screening of antimicrobial peptides. Curr Pharm Des. 2010;16(28):3204-11.
8. B Guixer. Chemically synthesized peptide libraries as a new source of BBB shuttles. Use of mass spectrometry for peptide identification. J Pept Sci. 2016 Sep;22(9):577-91.

Introduction:

In the rapidly advancing field of medicine, researchers are increasingly intrigued by proteins and peptides. As vital signaling molecules and potential drug candidates, the synthesis and customization of peptides have become pivotal. This article delves into the realm of custom peptide library synthesis, analyzing its significance in medical research and the latest advancements.

Custom Peptide Library Design and Construction:

The design and construction of peptide libraries are critical steps in custom peptide library synthesis. This section explores how to design libraries based on research needs, selecting suitable synthesis strategies and technologies. Topics covered include peptide sequence design, method selection, and quality control measures such as purity and mass spectrometry.

Applications of Custom Peptide Libraries in Drug Development:

Custom peptide library synthesis plays a crucial role in drug development. This section extensively discusses the use of custom peptide libraries in identifying potential drug targets, screening drug candidates, and enhancing drug specificity and efficacy. Through case studies, it illustrates successful experiences and future directions in drug development utilizing custom peptide libraries.

Technological Innovations and Trends:

Peptide synthesis technology continually undergoes innovation and development. This section tracks the latest technological trends, including but not limited to solid-phase synthesis, liquid-phase synthesis, and genetic engineering techniques. By evaluating new technologies, it provides researchers with insights to choose the most suitable peptide synthesis method for their research purposes.

Applications of Custom Peptide Libraries in Disease Research:

Beyond drug development, custom peptide libraries play a crucial role in disease research. This section delves into the applications of custom peptide libraries in areas such as cancer, neurological disorders, immune system diseases, presenting case studies and revealing new biological mechanisms discovered through custom peptide library research.

Challenges and Future Outlook:

Despite significant achievements in custom peptide library synthesis, challenges persist. This section discusses current technical, economic, and ethical challenges, offering insights into potential future developments. It explores avenues such as automation, big data analysis, and personalized medicine applications.

Conclusion:

Through a comprehensive analysis of custom peptide library synthesis, this article underscores its significance in medical research and drug development. It serves as a guide for researchers, providing an in-depth understanding and application framework for custom peptide library synthesis technology.

By dissecting the field of custom peptide library synthesis, this article aims to offer a thorough understanding and application guide, fostering continuous innovation and development in this critical domain.

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Part1 Financing/BD Event

December 2023

• Kintide Pharmaceuticals completed US$8 million in seed round financing to advance a highly integrated computational design-automated synthetic peptide drug discovery platform
• Roche acquires Carmot Therapeutics for over US$3 billion, entering the GLP-1 competition
• Fractyl Health said in a regulatory filing that it plans to conduct an IPO in 2024. The company is committed to developing innovative treatments for type 2 diabetes and obesity, and the funds raised will be used to advance the development of its pipeline, including a gene therapy that expresses a GLP-1 receptor agonist in the pancreas.
• Amide Technologies announced that it has begun commercializing its novel peptide manufacturing platform and has completed  in financing, including a  Series A+ round led by Engine Ventures with participation from Forcefield Venture Fund. It previously raised a $3.55Mn Series A round led by Engine Ventures and a $5.45Mn Seed round led by Biological Engineering Ventures.
• Alkermes plc announced that it has entered into a definitive agreement to sell its development and manufacturing facility in Athlone, Ireland, to Novo Nordisk. Under the terms of the agreement, upon completion of the transaction, Alkermes will be entitled to a one-time cash payment of  for the facility and associated assets, subject to customary adjustments in accordance with the agreement.

November 2023

• Zhifei Biotech plans to acquire 100% equity of Chongqing Chenan Biopharmaceutical Co., Ltd. in cash to enter the GLP-1 field
• Chengdu Taihe Weiye Biotechnology Co., Ltd. completed nearly 300 million yuan in Series A+ financing to accelerate the company’s Fmoc amino acid production capacity construction
• Peptide Biotech completed nearly 200 million yuan in Series B+ financing to promote the development of GLP-1 products
• lmagine Pharma completed US$32.5 million in Series A financing to develop new peptide IMG-1 and other projects

September 2023

• PeptiDream enters into a new multi-target collaboration and licensing agreement with Genentech, a Roche company, to discover and develop novel macrocyclic peptide-radioisotope (peptide-RI) conjugates
• Elicio Therapeutics receives $2.6 million foundation grant to fund research into two therapeutic cancer peptide vaccines
• Shenzhen Tuosheng Biotechnology Co., Ltd. announced the completion of tens of millions of RMB Pre-A round of financing

August 2023

• PeptiGrowth Inc (PeptiGrowth) and Orizuru Therapeutics, Inc (OZTx) have signed a joint development agreement to create a new synthetic peptide to replace recombinant growth factors used in the production of regenerative medicine products
• HBC lmmunology completed US$900,000 in seed round financing to advance the research and development of peptide drugs

June 2023

• Sino Biopharmaceuticals and Hongyun Huaning (Hangzhou) Biopharmaceutical Co., Ltd. have reached a cooperation agreement to jointly develop the dual-target innovative weight loss drug GMA106. GMA106 is a dual-target drug mainly suitable for the treatment of obesity, non-alcoholic fatty liver disease and diabetes

May 2023

• Carmot Therapeutics announces raising $150 million in super Series E funding to advance its development of treatments for obesity and diabetes
• lronwood successfully acquires next-generation GLP-2 through acquisition of VectivBio for $1 billion

Annual Highlights of Blockbuster Products

December 2023

• Eli Lilly announced that its injectable Zepbound (Tirzepatide) is now available in U.S. pharmacies
• Lisata Therapeutics announced that it has completed enrollment in the Phase IIb ASCEND study of its novel drug LSTA1 for the treatment of metastatic pancreatic ductal adenocarcinoma (“mPDAC”), achieving a key milestone.
• Italian company Nerviano Medical Sciences (NMS) and Spanish pharmaceutical company Italfarmaco (ITF) jointly announced that ITF will use NMS’s proprietary linker-payload technology to develop a new PDC product candidate.
• Apellis presented post-hoc data for its bicyclic peptide drug EMPAVELI® (pegcetacoplan) at the ASH Annual Meeting that strengthen the efficacy of EMPAVELI (pegcetacoplan) in adults with paroxysmal nocturnal hemoglobinuria (PNH) for up to three years. years of long-term efficacy and safety.

November 2023

• Eli Lilly announced that its GIP/GLP-1 receptor dual agonist Zepbound (Tirzepatide) has been approved by the U.S. FDA to reduce weight and maintain weight stability in obese or overweight adult patients.
• Novo Nordisk released its results for Q3 and the first three quarters of 2023. Sales of semaglutide in the first three quarters have exceeded US$14.2 billion.
• Eli Lilly and Company released its financial report for the third quarter of 2023. Sales of Tirzepatide in the first three quarters have reached US$2.957 billion.

October 2023

• Novo Nordisk announced that the Phase III clinical study FLOW of semaglutide in patients with type 2 diabetes and chronic kidney disease with renal insufficiency was terminated early due to excellent efficacy.

August 2023

• Eli Lilly’s Tirzepatide Injection Submits Registration Application in China for Long-term Weight Management Indication in Adults

July 2023

• Eli Lilly announced the results of two phase 3 clinical trials on tilpotide. The results showed that the average weight loss effect was as high as 26.6%, making it the most powerful weight loss drug in history.

Peptide drugs approved for marketing

December 2023

• Tonghua Dongbao Pharmaceutical’s marketing application for biosimilar GLP-1 analog liraglutide injection filed under registration classification 3.3 has been approved
• Ascendis Pharma announced that the FDA has accepted the company’s resubmitted New Drug Application for palopegteriparatide (TransCon PTH) for the treatment of adult patients with hypoparathyroidism.
• The National Medical Insurance Administration officially announced the adjustment list of the 2023 version of the National Medical Insurance Drug Catalog. The new round of medical insurance catalog includes four popular GLP-1 products. These include Renhui Biotech’s benaglutide injection, Lilly’s dulaglutide injection, Hanson Pharmaceuticals’ polyethylene glycol loxenatide injection, Novo Nordisk’s semaglutide injection, etc.

September 2023

• BioLineRx announces FDA approval of Aphexda (motixafortide) combined with filgrastim (granulocyte colony-stimulating factor G-CSF) to mobilize hematopoietic stem cells into the peripheral blood as a stem cell mobilization (SCM) to promote autologous transplantation in patients with multiple myeloma at the time of transplantation
• The marketing application for new indications of Lilly’s dulaglutide injection (trade name: Duida) was approved

July 2023

• Renhui Biotech’s benaglutide has been approved for marketing as a new indication for weight loss. This is the first original new weight loss drug in China, and the injection frequency is three times a day.
• East China Medicine’s Liraglutide Injection is approved for marketing for obesity or overweight indications

June 2023

• Hansoh Pharmaceutical’s Class 1 new drug “Pemoxatide Injection” (trade name: Saint Relais) was approved for marketing. This medicine is suitable for adult non-dialysis patients who are not receiving erythropoiesis stimulating agents (ESA), and adult dialysis patients who are receiving short-acting erythropoietin (EPO).

May 2023

• Blue Earth Diagnostics’ radiohybrid prostate-specific membrane antigen (PSMA)-targeted PET imaging agent Posluma (flotufolastat F 18) injection (formerly known as 18F-rhPSMA-7.3) was approved by the FDA for marketing

March 2023

• Acadia Pharmaceuticals Announces FDA Approval of DAYBUE (trofinetide) for the Treatment of Rett Syndrome in Adult and Pediatric Patients Two Years and Older
• Cidara Therapeutics’ New Drug Application (NDA) for Rezafungin for the treatment of candidemia and invasive candidiasis was approved by the FDA

January 2023

• Radius Health’s TYMLOS (abapatide) received U.S. FDA approval for new indication (osteoporosis)

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