Engineering Protease-Resistant Peptides to Inhibit Human Parainfluenza Viral Respiratory Infection

Abstract

The lower respiratory tract infections affecting children worldwide are in large part caused by the parainfluenza viruses (HPIVs), particularly HPIV3, along with human metapneumovirus and respiratory syncytial virus, enveloped negative-strand RNA viruses. There are no vaccines for these important human pathogens, and existing treatments have limited or no efficacy. Infection by HPIV is initiated by viral glycoprotein-mediated fusion between viral and host cell membranes. A viral fusion protein (F), once activated in proximity to a target cell, undergoes a series of conformational changes that first extend the trimer subunits to allow insertion of the hydrophobic domains into the target cell membrane and then refold the trimer into a stable postfusion state, driving the merger of the viral and host cell membranes. Lipopeptides derived from the C-terminal heptad repeat (HRC) domain of HPIV3 F inhibit infection by interfering with the structural transitions of the trimeric F assembly. Clinical application of this strategy, however, requires improving the in vivo stability of antiviral peptides. We show that the HRC peptide backbone can be modified via partial replacement of α-amino acid residues with β-amino acid residues to generate α/β-peptides that retain antiviral activity but are poor protease substrates. Relative to a conventional α-lipopeptide, our best α/β-lipopeptide exhibits improved persistence in vivo and improved anti-HPIV3 antiviral activity in animals.

Potency of Fusion-Inhibitory Lipopeptides against SARS-CoV-2 Variants of Concern

“…The efficacy of SARS-CoV-2-inhibitory peptides at blocking viral transmission ( 7 , 19 , 20 ), taken together with our published data for other viruses ( 21 – 26 ), suggests that an effective antiviral effect can be achieved via administration of antiviral peptides. The potency of these lipopeptides for neutralization of SARS-CoV-2 VOCs is substantial and consistently observed across the VOCs.…”

Advance in Hybrid Peptides Synthesis

“…The introduction of a heterogeneous backbone of β ‐amino acids increases the number of possible foldamers exponentially, which greatly increases the possibilities to discover functional α / β ‐foldamers to mimic the structure and function of native peptides. A sequence‐based design method [ 41,80,81 ] was applied to design α / β ‐peptide foldamers with protein recognition and binding functions, as well as significantly improved stability against proteolysis [ 38,39 ] (Figure 6b,c). In addition, such α / β ‐peptide foldamers also have broad application prospects as catalysts for chemical reactions [ 34–36 ] and as mimics of antimicrobial peptides.…”

“…[25][26][27] 𝛼/𝛽-peptides and peptide/peptoid hybrids, specifically 𝛼peptide/𝛼-peptoid hybrids in this review, are two typical DOI: 10.1002/marc.202200575 hybrid peptides containing 𝛽-amino acid and N-substituted glycine residues, respectively. The additional rotatable bond of 𝛽-amino acids allows more possibilities for the conformation of 𝛼/𝛽-peptides, which promotes diverse applications in foldamer design, [28][29][30][31][32][33] catalysis, [34][35][36] protein binding, [37][38][39][40][41][42] and antimicrobials. [43][44][45] On the other hand, the N-substitution of peptoid residues provides more structural diversity of peptide/peptoid hybrids, which also enables applications in protein binding, [46][47][48][49] antimicrobials [50][51][52][53] and drug delivery.…”

β-Peptides incorporating polyhydroxylated cyclohexane β-amino acids: synthesis and conformational study

“…[1][2][3][4][5][6] In addition, their resistance to protease degradation 7,8 is beneficial for therapeutic applications. 4,[9][10][11][12][13][14] Carbocyclic β-amino acids are of special interest due to the limited flexibility derived from their constrained cyclic structures and have been demonstrated to act as particularly strong helix or turn inducers. 5,[15][16][17] This has led, for instance, to the design of bioactive β-peptides [18][19][20] , or self-assembling nanomaterials [21][22][23][24] and catalysts.…”