Poly(N-vinylpyrrolidone) Antimalaria Conjugates of Membrane-Disruptive Peptides

Abstract

The concepts of polymer–peptide conjugation and self-assembly were applied to antimicrobial peptides (AMPs) in the development of a targeted antimalaria drug delivery construct. This study describes the synthesis of α-acetal, ω-xanthate heterotelechelic poly­(N-vinylpyrrolidone) (PVP) via reversible addition–fragmentation chain transfer (RAFT)-mediated polymerization, followed by postpolymerization deprotection to yield α-aldehyde, ω-thiol heterotelechelic PVP. A specific targeting peptide, GSRSKGT, for Plasmodium falciparum-infected erythrocytes was used to sparsely decorate the α-chain ends via reductive amination while cyclic decapeptides from the tyrocidine group were conjugated to the ω-chain end via thiol–ene Michael addition. The resultant constructs were self-assembled into micellar nanoaggregates whose sizes and morphologies were determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The in vitro activity and selectivity of the conjugates were evaluated against intraerythrocytic P. falciparum parasites.

Antiplasmodial Cyclodecapeptides from Tyrothricin Share a Target with Chloroquine

“…Previously Rautenbach et al [ 36 ] observed that the natural Trc mixture, individual purified Trc analogues, and specifically TrcA, had significantly higher antiplasmodial activity than the analogous GS, with IC 50 ’s ranging between 0.6 and 460 nM against the CQS P. falciparum 3D7 strain. Similarly, Jokonya et al [ 38 ] found that the Trc mixture had an IC 50 of 1.1 nM against the CQS P. falciparum NF54 strain.…”

“…This indicated that the variable pentapeptide in the Trcs have a major influence on the anti- Plasmodium activity. However, some inherent systemic toxicity of the Trcs still remain, which Jokonya et al [ 38 ] addressed in a “smart” pH triggered nano-conjugate containing the Trcs linked to poly(N-vinylpyrrolidone). In this study, the hemolytic toxicity was lowered by nearly 20-fold in the nano-formulation while a low nanomolar activity was maintained against a CQS P. falciparum strain.…”

Peptide–Polymer Conjugates: A Promising Therapeutic Solution for Drug-Resistant Bacteria

“…The polymerization involves initiators and macromonomers, and has some advantages that coupling does not have. With ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs), single-electron-transfer living radical polymerization, nitroxide-mediated radical polymerization, atom transfer radical polymerization (ATRP), reversible addition-fragmentation chain transfer, ROP of other monomers, and other methods, the polymerization can synthesize PPC with long polypeptide chains and various macromolecular structures [51,[59][60][61][62]. Among them, NCA-ROP provides a convenient way to synthesize PPC, which have various macromolecular structures, such as linear polymer, star copolymer, dendritic copolymer, and hyperbranched polymer, and has attracted more and more attention [63].…”

Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure

“…The involvement of redox-active metabolites in both efficacy and toxicity suggested that the two activities may be mechanistically linked and inseparable (30). Earlier preclinical efforts to reduce the toxicity of 8-AQ via formulation or delivery approaches have not demonstrated an increase in the therapeutic window (31)(32)(33)(34)(35). However, a recent study in healthy Thai women suggested that even a relatively small improvement in the therapeutic index may be clinically meaningful and allow use of TQ in G6PDdeficient patients.…”