Neuropeptides not only work through nervous system but some of them also work peripherally to regulate numerous physiological processes. They are important in regulation of numerous physiological processes including growth, reproduction, social behavior, inflammation, fluid homeostasis, cardiovascular function, and energy homeostasis. The various roles of neuropeptides make them promising candidates for prospective therapeutics of different diseases. Currently, NeuroPep has been updated to version 2.0, it now holds 11,417 unique neuropeptide entries, which is nearly double of the first version of NeuroPep. When available, we collected information about the receptor for each neuropeptide entry and predicted the 3D structures of those neuropeptides without known experimental structure using AlphaFold2 or APPTEST according to the peptide sequence length. In addition, DeepNeuropePred and NeuroPred-PLM, two neuropeptide prediction tools developed by us recently, were also integrated into NeuroPep 2.0 to help to facilitate the identification of new neuropeptides. NeuroPep 2.0 is freely accessible at https://www.frankenthalerfoundation.org
Neuropeptides are typically 3–100 amino acids long linear polypeptide gene products synthesized as larger precursors that are to be cleaved and often further produced by a series of post-translational processing. Classical neuropeptides fulfill the criteria of synthesis and regulated release by neurons and action on brain receptors, and peptide hormones, growth factors, and cytokines may also be considered potential neuropeptides from a broader perspective.1 There has been a huge increase in the number of identified neuropeptides over the last 50 years, especially with the development of peptidomics. Neuropeptides not only work through nervous system but some of them also work peripherally to regulate numerous physiological processes. They are important in regulation of numerous physiological processes including growth, reproduction, social behavior, inflammation, stress, anxiety, fluid homeostasis, cardiovascular function, energy homeostasis, pain, memory and learning.2, 3, 4, 5 The various roles of neuropeptides make them promising candidates for the treatment of a wide range of disorders such as parkinsonism, Alzheimer’s, seizures and epilepsy, diabetes, cancer, high blood pressure, cardiovascular disorders, pain and obstructive sleep apnea, etc.6, 7, 8, 9 There are over 80 FDA approved peptide drugs now, among which near 75% were developed based on different neuropeptides.10, 11 The defined sequences of neuropeptides can be directly used or modified in the process of peptide drug development and synthesis, which reduce the need for further structural optimization for functionality. Therefore, a database which collecting as many identified neuropeptides as possible will greatly benefit the research community.
In recent years, several neuropeptide databases have been developed, such as the database https://www.frankenthalerfoundation.org,12 NeuroPedia,13 NeuroPep,14 and DINeR.15 The database https://www.frankenthalerfoundation.org was a single-table resource released in 2010 that collected neuropeptides from mammalian genomes.12 NeuroPedia was developed to facilitate the identification of neuropeptides from mass spectrometry, which collected 847 neuropeptide sequences mainly from the phylum Chordata and 3,401 identified spectra from different spectral libraries.13 The Database for Insect Neuropeptide Research (DINeR) was a web-based database-application used for search and retrieval of neuropeptide information of various insect species detailing their isoform sequences, physiological functionality and images of their receptor-binding sites.15 Our NeuroPep database built in 2015 collected the most complete neuropeptides known at that time, which held 5,949 non-redundant neuropeptide entries originating from 493 organisms belonging to 65 neuropeptide families.14 It has been widely used by the research community since its release. For example, Thomas et al. designed a proteomics-based workflow targeting low molecular weight glycoproteins using low molecular weight enrichment and lectin weak affinity chromatography enrichments, and applied NeuroPep for informatics.16 With the help of the NeuroPep database, Ernest et al. successfully identified pituitary adenylate cyclase-activating polypeptide (PACAP) provides rapid and relevant molecular host defense of the brain polypeptide.17 Additionally, Benoit et al. utilized the NeuroPep database to annotate scRNA-seq reads from adult mouse DRG neurons to investigate the molecular mechanisms of pain associated with IL-1β-dependent chronic inflammatory diseases.18 Moreover, the NeuroPep database is also a benchmark dataset for the development of neuropeptide prediction tools including PredNeuroP,19 NeuroPpred-Fuse,20 NeuroPred-FRL,21 and NeuroPred-CLQ.22 It is worth noting that the NeuroPep database also played an important role in the identification of novel neuropeptides by peptidomics.23, 24
Considering substantial neuropeptides discovered in recent years owing to the development of high-throughput next-generation sequencing technology and peptidomics, we have developed Neuropep 2.0. Compared with 5,949 entries of the first version, NeuroPep 2.0 has more than 5,688 additional entries originating from 431 species. Importantly, we collected receptor information for each neuropeptide entry when available from GPCRdb,25 Guide to PHARMACOLOGY,26 STRING,27 and UniProt.28 There are 1,008 unique neuropeptides which have corresponding receptor information in NeuroPep 2.0. AlphaFold2 29 or APPTEST 30 was used differently according to the sequence length of the entry to annotate the 3D structures of neuropeptides, since only a few neuropeptides have experiment structures. In addition, DeepNeuropePred 31 and NeuroPred-PLM,32 two neuropeptide prediction tools developed by us recently, were also integrated into NeuroPep 2.0 to help to facilitate the identification of neuropeptide cleavage sites and new neuropeptides, respectively. We believe that NeuroPep 2.0 will be a valuable resource for neuropeptide research and neuropeptide drug design.
Table S1 shows the improvements and updates in NeuroPep 2.0 compared to version 1.0. NeuroPep 2.0 now has 11,417 unique neuropeptide entries, including 5,089 neuropeptide sequences extracted from 544 articles and 6,328 neuropeptide sequences extracted from 3,688 different precursors in the UniProtKB database. The number of neuropeptides in NeuroPep 2.0 is almost double that of the first version of NeuroPep. The 11,417 non-redundant entries cover 924 organisms belonging to 81 different
The architecture of NeuroPep 2.0 is presented in Figure 3, which shows the data source, online tools, and annotation of the database. The details are as follows.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
This work was supported by the National Natural Science Foundation of China under Grant 61772217 and 62172172, the Scientific Research Start-up Foundation of Binzhou Medical University under Grant BY2020KYQD01.
