Neurotrophin mimetics and neurotrophin peptidomimetics provide an encouraging edge in therapeutic interventions for neurological disorders, as an innovative approach to utilize the potential of neurotrophins for treating different neurological diseases.(p1),(p2) Neurotrophins belong to a protein family necessary for neuron growth, maintenance, and survival, which ultimately helps with neuroregeneration and neuroplasticity. However, the limited therapeutic applications of neurotrophins due to several disadvantages, viz. no capacity to cross the blood–brain barrier (BBB), associated adverse side effects, and pleiotropic effects, have prompted the advancement of peptidomimetics as a more practical alternative.(p1),(p2),(p3)
Peptidomimetics are specially engineered compounds replicating the structural and functional properties of peptides.(p4) Nonpeptidic components are often incorporated to improve their stability, bioavailability, and specificity for receptors. According to Grossman's definition, peptidomimetics are synthetic agents designed to mimic the binding sites of peptides to interfere with protein–protein interactions.(p4) These molecules aim to address the shortcomings of natural peptides, such as their limited metabolic stability and rapid degradation, while preserving or enhancing their biological efficacy.(p5),(p6),(p7) The neurotrophin mimetics have therapeutic potential for a range of neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD).(p5),(p6),(p7)
Considering the complexity of neurological diseases, few of the ongoing preclinical and clinical studies focus on repurposing peptidomimetics for neurodegeneration, where these agents were initially developed for treating other diseases.(p8),(p9) Repurposing existing peptidomimetic drugs for other diseases [such as neurodegenerative diseases (NDs)] offers a shortcut to drug development as the safety profiles of these drugs are already known. However, extensive clinical trials are required to validate their efficacy and potency in treating specific neurological conditions.
This review article briefly discusses neurotrophins, their signaling mechanism inducing neuritogenesis, their therapeutic role in treating NDs, and the limitations associated with their therapeutic application. The main aim of this review article is to highlight the importance of emerging neurotrophin peptidomimetics as therapeutic alternatives to endogenous neurotrophin molecules, given their various limitations, for clinical use.
A class of endogenous soluble proteins known as neurotrophins share structural and functional similarities and significantly impact vertebrate neural development.(p10),(p11),(p12) Levi-Montalcini and associates discovered the first neurotrophin, i.e. nerve growth factor (NGF), in 1951. The neurotrophin family consists of NGF,(p11) brain-derived neurotrophic factor (BDNF),(p13) neurotrophin-3 (NT-3),(p14) and neurotrophin-4/5 (NT-4/5).(p15),(p16) Other than these neurotrophins, two neurotrophins
Neurotrophins, being secreted proteins, begin their synthesis as pre- and proneurotrophins (Pro-NTs) within the rough endoplasmic reticulum (RER). The presequence guides the initial synthesis of neurotrophin molecules to the RER.(p19),(p20) Pro-NTs, the precursor forms of neurotrophins, undergo complex secretion and processing, which is essential for their maturation and biological function.(p21) Upon entering the endoplasmic reticulum, the presequence is promptly removed, allowing Pro-NTs to
The binding of neurotrophins to transmembrane receptors from the tyrosine kinase receptor family, such as tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), and tropomyosin-related kinase C (Trk C), is the mechanism of neuritogenesis.(p25),(p26) Neurotrophins also bind to the receptor of the tumor necrosis factor (TNF) superfamily known as the p75 neurotrophin receptor (p 75NTR)(p25),(p26) and mediate pro-NT signaling (converting precursors to mature NTs).(p27) NGF and
Research on neurotrophins has recently focused on proNGF and proBDNF. Although significantly fewer studies have explored proNT-3, there has been a notable lack of investigation of the function of proNT-4/5 in facilitating cellular apoptosis.(p40) The functions attributed to the p 75NTR receptor are complex and diverse.(p41),(p42) p 75NTR has been shown to support cell survival and initiate apoptosis, encourage neurite outgrowth while aiding in the collapse of the growth cone, and mediate
Mature NTs are symmetrical homodimers, with each promoter comprising 118–119 amino acids. These promoters feature seven β-turn loops that are exposed on the exterior (loops 1, 2, and 4), along with an additional exposed loop (loop 3) that contains three consecutive reverse turns (Figure 4). Both the C- and N-termini, as well as a β-strand segment, are also solvent accessible. These accessible regions are likely crucial for interactions with neurotrophin receptors due to their structural
NDs are marked by the progressive decline of neurons in the central nervous system (CNS) and pose a significant public health challenge, affecting the quality of life of the ageing population.(p46) Critical features of NDs include the misfolding and aggregation of neurotoxic proteins, neuroinflammation, mitochondrial and vascular dysfunction, and synaptic failure.(p47) These conditions, including AD, PD, and Huntington's disease (HD), result in significant neuronal damage characterized by
Even though endogenous neurotrophin molecules have shown promising effects in preclinical studies with respect to their potential therapeutic applications in NDs, several challenges restrict their successful implementation. Some of the difficulties associated with the therapeutic application of endogenous neurotrophins in the treatment of NDs include poor pharmacological properties (low stability in serum), short half-lives (requirement for frequent administration, which can lead to potential
The clinical application of neurotrophins is limited by several factors, including their poor pharmacokinetics, inability to cross the BBB, and potential side effects. It is therefore imperative that these obstacles be removed for neurotrophins to be successfully applied therapeutically. Numerous tactics have been proposed to improve the pharmacokinetics of endogenous neurotrophins. These include the synthesis of synthetic peptides (peptidomimetics) that bind to particular receptors or mimic
The word 'mimetic' in neurotrophin mimetic is broadly used to refer to a modulator with structural features similar to neurotrophic factors and the properties of neurotrophin molecules. A group of mimetics might act as receptor agonists(p6),(p74) or antagonists.(p74),(p75) However, some groups of mimetics bind in a noncompetitive manner at neurotrophin receptors, upregulating or downregulating their activity to change the expression of different cellular proteins to induce neuritogenesis.(p3),
Longo _et al._ (1990)(p76) were the first to show that the peptide NGF mimetic C5 (β-turn of NGF loop 1; KGKE amino acid residues), which is a small cyclized dimeric peptide, exerts p 75NTR-dependent neurotrophic activity and inhibits neuronal death.(p76) Another peptide, CATDIKGAEC (1.5 kDa), a mimetic of the NGF domain (homologous to the mutated NGF-β hairpin loop), was verified to trigger a neurotrophic response after binding to the p 75NTR receptor (p 75NTR antagonist) and protects neurons from
An increasing number of preclinical and clinical trials suggest that altering BDNF–TrkB signaling can be advantageous in the treatment of neurological diseases and injuries.(p105) Consequently, considerable research has focused on developing peptidomimetics of BDNF, which specifically binds to TrkB and encourages synaptic function, neuronal survival, and differentiation.(p7),(p106) In recent years, the research focus has intensified toward peptidomimetics to BDNF loops 2 and 4 as therapeutic
In a previous study,(p126) the synthesis and physiochemical and biological characteristics of a peptide comprising the initial 13 residues of NT-3 were reported. The NT-3(1–13) peptide demonstrated the ability to promote neurite outgrowth and axonal branching through a downstream mechanism that increases CREB, thereby confirming its protein-mimicking behavior. The experiment was carried out in the SH-SY5Y cell line using a dosage of 100 µM of NT-3(1–13).(p126)
In another study, a
The technique in which an existing drug used for treating a particular disease is used as a new treatment for a disease that it was not originally designated for is known as drug repurposing. This approach comprises three sequential steps: first, identification of the drug; second, assessment of its efficacy through preclinical models; and finally, progression to Phase II clinical trials. The advantage of using this technique is that the drug can be used directly in clinical and preclinical
The signaling pathways associated with P 75NTR closely overlap with the degenerative networks involved in AD. The peptidomimetic drug LM11A-31 alters the activity of P 75NTR and has demonstrated the ability to decrease the loss of synapses caused by amyloid and pathological tau in preclinical models.
LM11A-31 is a peptidomimetic designed to mimic NGF β-hairpin loop I, a domain crucial for the interaction of NGFs with P 75NTR. It acts as a modulator of P 75NTR signaling, helping to downregulate its
The potential of neurotrophic factors to regulate neuronal cell survival in the developing nervous system and treat NDs has been a research focus. Peptidomimetics have emerged as a significant class of therapeutics in this context. However, several challenges must be addressed before they can become effective therapeutic agents. Preclinical data indicate that subcutaneous or intravenous administration of neurotrophic factors might offer therapeutic benefits for PNS and CNS diseases. Despite
It is commonly recognized that neurotrophins support and enhance the nervous system. Their capacity to elicit prosurvival and profunctional responses in PNS and CNS nerve cells makes them a promising therapeutic candidate for treating neurodegenerative illnesses. Nevertheless, there are a lot of challenges to be solved before neurotrophins can be used therapeutically. The challenges associated with treating endogenous neurotrophins in past clinical trials led to the discovery of
DM received senior research fellowship from the SERB project, and RM received an junior research fellowship from IASST. The authors thank Dr. Glenn F. King, Institute of Molecular Biosciences, University of Queensland Australia, for critically reading and editing the manuscript. This work was funded by the Science and Engineering Research Board, under DST, Govt. of India, New Delhi ( EMR/2017/001829 ) and a Core Research Grant from IASST to AKM.
The authors declare that they have no known
Dev Madhubala earned BSc (biotechnology) in 2015 from St. Xavier College, Ranchi University, Ranchi, India, and MSc (life science specialization in biochemistry) in 2017 from Central University of Punjab, Bathinda, Punjab, India. Currently she is enrolled in the PhD program in the Department of Molecular Biology and Biotechnology, at Tezpur University. Her research interest is snake venom nerve growth factor-derived peptide therapeutics in preventing neurodegenerative diseases.
Rosy Mahato earned BSc (zoology) in 2018 from Pragjyotish College, Gauhati University, Assam, India, and MSc (zoology specialization in entomology) in 2021 from Dakshin Kamrup College, Gauhati University, Assam, India. Currently, she is enrolled in the PhD program in Microbial Biotechnology and Protein Research Laboratory under Life Sciences division at the Institute of Advanc
