Penetrating the Blood-Brain Barrier with New Peptide–Porphyrin Conjugates Having anti-HIV Activity

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.

Antiviral Peptide-Based Conjugates: State of the Art and Future Perspectives

“…Moreover, in some cases ( Table 2 , entries 11–19), sequences with membrane-permeating characteristics are used as prodrugs/substrate recognition motifs for proteases. Finally, the majority of CPPs in Table 2 are linear, of L-chirality, cationic or amphipathic; to the best of our knowledge, only two reports on antiviral PDCs based on anionic CPPs have appeared [ 82 , 83 ].…”

“…While the N-terminus of the CPP—elongated or not via an intervening spacer unit—is rather usual, alternative approaches, e.g., by way of an extra residue (often Lys or Cys) at either (N- or C-) end of the proper CPP sequence are also favored. Recent work has shown that whichever of these attachment modes is used can have a significant impact on conjugate performance [ 82 , 83 ]. The conjugate end-product should ideally be non-cytotoxic, non-immunogenic and have minimal interference (hence adverse reactions) with other drugs in multi-therapy schedules.…”

Bioinspired porphyrin–peptide supramolecular assemblies and their applications

“…Porphyrin and peptide molecules can be connected by covalent bonds through chemical coupling, or they can form supramolecular assembly systems through non-covalent interactions. 17,32,[72][73][74] Naturally existing porphyrin derivatives exert their unique biological and physiological functions in a specific arrangement under the action of polypeptides. Selecting a polypeptide-modified porphyrin compound with a specific amino acid sequence, and using the self-assembly of the polypeptide molecule to regulate the interaction between the porphyrin molecules in the system, is also a key step in the design and synthesis of polypeptide-modified porphyrin compounds.…”

Therapeutic potential of pyrrole and pyrrolidine analogs: an update

“…Apart from this, pyrrole and pyrrolidine analogs have diverse therapeutic applications like fungicides, antibiotics, anti-inflammatory drugs, cholesterol-reducing drugs, anti-tubercular, and antitumor agents [ 20 – 25 ]. These are also known to inhibit reverse transcriptase in case of human immune deficiency virus type 1 (HIV-1) and cellular DNA polymerases protein kinases [ 26 , 27 ]. The combination of different pharmacophore in a pyrrole and pyrrolidine ring system has led to more active compounds [ 28 – 32 ].…”