Age-Related Macular Degeneration (AMD) is a multifaceted retinal degenerative disease. It stands as a primary cause of blindness in the elderly population [1]. With the passage of time, the prevalence of AMD steadily increases each year. Projections suggest an alarming surge, with an anticipated 288 million affected individuals by 2040 [2], [3], highlighting AMD as a paramount concern in the global landscape of public health.

The hallmark of wet AMD (wAMD) is the abnormal growth of choroidal neovascularization (CNV), followed by subsequent leakage or bleeding, resulting in pathological changes in the macula and posing a threat to visual acuity. Over the last decade, intravitreal administration of anti-vascular endothelial growth factor (VEGF) agents, exemplified by ranibizumab [4] and aflibercept [5], have held its position as the primary therapeutic approach for wAMD. While these anti-VEGF drugs have undeniably made substantial strides in enhancing visual acuity, their clinical utility faces several formidable challenges [6], [7]. These challenges encompass the considerable financial burden associated with treatment, the need for frequent injections, and the issue of suboptimal patient compliance. Furthermore, it is paramount to recognize that VEGF plays a pivotal role in the viability of choroidal endothelial cells and optic nerve cells. Consequently, prolonged intravitreal administration of anti-VEGF drugs raises concerns regarding the potential for inducing anomalous retinal blood vessel development and inflicting damage upon retinal neurons [8], [9].

CC motif chemokine receptor 3 (CCR3), a member of the chemokine receptor family, is characterized as a seven-transmembrane G-protein-coupled receptor (GPCR) featuring seven alpha-helical transmembrane domains rich in hydrophobic amino acids, as well as an intracellular C-terminal domain and an extracellular N-terminal domain [10]. Eotaxin serves as an endogenous ligand for CCR3. In both in vitro and in vivo investigations, eotaxin has demonstrated its capacity to induce angiogenesis [11], positioning it as a prospective serum biomarker for AMD. Studies have discerned a distinctive expression of CCR3 within the choroidal region of AMD patients. Remarkably, antagonizing CCR3 yields substantial inhibition of CNV formation, all without compromising the structural and functional integrity of the retina [12], [13]. These findings underscore the potential for CCR3 blockade to serve as a secure and effective adjunct to the current armamentarium for AMD treatment, offering promising avenues for both research and clinical applications.

CCR3 serves as the pivotal determinant of its ligand binding selectivity. Remarkably, agents binding to this region, with the potential to interfere with eotaxin receptor recognition, hold promise as effective CCR3 blockers [14]. There are also investigators and companies that developed directly target CCR3 small molecule antagonists, and there are several preclinical data showing that CCR3 antagonists have inhibitory effects on CNV [15], [16]. AKST4290, a small molecule drug targeting CCR3 for the treatment of AMD, is effective not only in treatment-naïve patients with wAMD, but also in patients who do not respond to anti-VEGF therapy [17]. Nevertheless, the high lipid solubility intrinsic to small molecules imparts a drawback in the form of limited selectivity and the risk of off-target toxicity. Clinical trials of several CCR3 small molecule antagonists have been slow or stalled, such as MT-0814, which terminated its Phase II clinical study in AMD in April 2020 due to safety concerns. These limitations pose obstacles to their application in ophthalmic diseases, accentuating the need for alternative strategies [18], [19].

In contrast, peptide drugs exhibit a suite of advantageous attributes. They are characterized by facile synthesis, strong controllability, high safety and biocompatibility, and an exceptional capacity to disrupt protein–protein interactions there by having emerged as potent therapeutic tools [20].Specifically, peptide drugs are constructed from natural amino acid constituents, employing conventional chemical synthesis techniques or biosynthetic methods. This lends them an inherent compatibility with biological systems, facilitating a more seamless interaction with molecular targets. Furthermore, the synthesis process is marked by its simplicity and manageability. These inherent traits not only expedite drug development and reduce associated costs but also empower the precise design of peptide drug structures and functions, culminating in heightened selectivity for specific targets. This, in turn, mitigates the risk of interference with non-target proteins and the attendant potential for off-target effects and adverse reactions. The structural diversity and flexibility inherent to peptide molecules further enhance their unique capacity to interfere with protein–protein interactions [21].

Therefore, the pursuit of peptide antagonists targeting CCR3 emerges as an ideal avenue for advancing the treatment of AMD. In the scope of this study, we have ingeniously designed peptide antagonists strategically poised to thwart CCR3 activation by interrupting the eotaxin/CCR3 axis [22], thereby offering a highly selective strategy for CCR3 antagonism, ultimately leading to the inhibition of CNV.