Prevention and treatment of SHIVAD8 infection in rhesus macaques by a potent d -peptide HIV entry inhibitor

Abstract

Cholesterol-PIE12-trimer (CPT31) is a potent d-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a simian-HIV chimeric virus AD8 (SHIVAD8) macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ∼2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising candidate for HIV prevention and treatment.

Computational Design of Potent D-Peptide Inhibitors of SARS-CoV-2

“…Note that a peptide viral entry inhibitor, fuzeon, has been approved for the treatment of HIV, 24 and a d -amino acid analogue of it has been in development. 25 Here, we develop novel D-peptide inhibitors of the RBD–ACE2 interaction using an in-house methodology for converting (L)-peptides to highly stable D-analogues after searching a mirror-image version of the PDB (D-PDB). 26 Two designs bound the RBD with affinities of 29 and 31 nM, respectively.…”

Zanamivir–Cholesterol Conjugate: A Long-Acting Neuraminidase Inhibitor with Potent Efficacy against Drug-Resistant Influenza Viruses

“…However, following IV administration, 1b exhibited dramatically extended persistence in the circulation compared with ZNV (Figure ), with a T 1/2 (7.6 h) approximately 25-fold longer than that of ZNV (0.3 h). Analysis of overall kinetics in the circulation also demonstrated the remarkable superiority of compound 1b over ZNV (Table S2), suggesting that cholesterol conjugation is an effective strategy to improve the pharmacokinetics of small molecules, as well as biomacromolecules. − …”

“…Cholesterol can bind to plasma lipoproteins and albumin. Nucleic acids or peptides conjugated to a cholesterol moiety showed markedly improved pharmacokinetic properties in vivo. − Furthermore, cholesterol is abundant in eukaryotic cell membranes. Cholesterol conjugation enabled spontaneous insertion of modified nucleic acids and peptides into lipid bilayers and their subsequent uptake by cells. − This membrane-targeting strategy could be particularly useful for increasing the antiviral efficacy of NAIs as they block the NA enzyme activity at the surface of infected cells and consequently the progeny virus release and spread. , ZNV was chosen for modification because it is more structurally similar to other NAIs compared to the natural NA substrate, sialic acid, and thus, derivatization of ZNV may reduce the likelihood of resistance development.…”

So Pathogenic or So What?—A Brief Overview of SIV Pathogenesis with an Emphasis on Cure Research

“…In fact, SHIV SF162P3 has had great success in vaccine and broadly neutralizing antibody studies [82,85,86]. Serial passage of a SHIV using HIV-1 Ada env resulted in SHIV AD8 and its derivatives, which have also been used in vaccine, antibody, and therapeutics studies with relative success [87][88][89]. Nonetheless, even the CCR5-tropic SHIVs are not necessarily ideal due to the use of env sequences from chronically infected PWH and their passaging in NHPs results in modified env sequences [82,84,90].…”