Abstract
Passing through the blood-brain barrier (BBB) to treat neurological conditions is one of the main hurdles in modern medicine. Many drugs with promising in vitro profiles become ineffective in vivo due to BBB restrictive permeability. In particular, this includes drugs such as antiviral porphyrins, with the ability to fight brain-resident viruses causing diseases such as HIV-associated neurocognitive disorders (HAND). In the last two decades, BBB shuttles, particularly peptide-based ones, have shown promise in carrying various payloads across the BBB. Thus, peptide–drug conjugates (PDCs) formed by covalent attachment of a BBB peptide shuttle and an antiviral drug may become key therapeutic tools in treating neurological disorders of viral origin. In this study, we have used various approaches (guanidinium, phosphonium, and carbodiimide-based couplings) for on-resin synthesis of new peptide–porphyrin conjugates (PPCs) with BBB-crossing and potential antiviral activity. After careful fine-tuning of the synthetic chemistry, DIC/oxyma has emerged as a preferred method, by which 14 different PPCs have been made and satisfactorily characterized. The PPCs are prepared by coupling a porphyrin carboxyl group to an amino group (either N-terminal or a Lys side chain) of the peptide shuttle and show effective in vitro BBB translocation ability, low cytotoxicity toward mouse brain endothelial cells, and low hemolytic activity. Three of the PPCs, MP-P5, P4-MP, and P4-L-MP, effectively inhibiting HIV infectivity in vitro, stand out as most promising. Their efficacy against other brain-targeting viruses (Dengue, Zika, and SARS-CoV-2) is currently under evaluation, with preliminary results confirming that PPCs are a promising strategy to treat viral brain infections.
Highlights
Peptide−drug conjugates (PDCs) have emerged as promising therapeutic tools for treating cancer and cardiovascular, brain, and infectious diseases, and others.[1]
In the last two decades, considerable efforts have been devoted to strategies enabling modulation and traversing of the blood-brain barrier (BBB).[6−11] Among them, peptide-based BBB shuttles have proven fruitful, with a number of sequences reported to effectively pass the BBB.[12−18] Recently, Neves et al showed that some domains of the Dengue virus type 2 capsid protein (DEN2C) can become effective BBB shuttles.[19]
Conjugation between porphyrins and peptides has received considerable attention in the past decade due to the enhanced properties of the newly generated species, including the ability to overcome some of the obstacles related to porphyrin application.[37,38,40,41]
Summary
Peptide−drug conjugates (PDCs) have emerged as promising therapeutic tools for treating cancer and cardiovascular, brain, and infectious diseases, and others.[1]. We report the on-resin synthesis of various new peptide−porphyrin conjugates (PPCs) with BBB-crossing ability and potential antiviral activity, and compare the effectiveness of activation methods (guanidinium, phosphonium, and carbodiimide) for coupling porphyrins to resin-bound peptides. The fact that the two sets of cross-peaks show approximately equal intensities indicates that the coupling reaction occurs with no regioselectivity Another concern of this work, of more practical consequence, was finding optimal conditions for high PPC yields by an on-resin approach. LC-MS analysis (Figure 2) of end products from the three activation protocols allowed some conclusions: (i) For guanidinium or phosphonium-mediated couplings, the conversion rate ratio of conjugate (two asterisks) to starting peptide (one asterisk) peak areas varies substantially across porphyrin/peptide combinations (Figure 2A,B,D,E; Table 2). 9 out of 14 conjugates, including MP-P5, P4-MP, and P4-L-MP, totally lacked hemolytic activity (Table 4)
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