HIV-1 drug discovery: targeting folded RNA structures with branched peptides

Abstract

Human immunodeficiency virus type 1 (HIV-1) is an RNA virus that is prone to high rates of mutation. While the disease is managed with current antiretroviral therapies, drugs with a new mode of action are needed. A strategy towards this goal is aimed at targeting the native three-dimensional fold of conserved RNA structures. This perspective highlights medium-sized peptides and peptidomimetics used to target two conserved RNA structures of HIV-1. In particular, branched peptides have the capacity to bind in a multivalent fashion, utilizing a large surface area to achieve the necessary affinity and selectivity toward the target RNA.

New Triazole-Containing Branched Bis(dipeptidomimetic) – Switching from Self-Dimerization to Anion-Binding Properties

“…Guest molecule was also found to bind strongly to the fragmented host in other fragmentation peaks (m/z = 548.34 and 958.46). The 1:1 binding stoichiometries in chloroform were also confirmed by 1 H NMR Job plot analysis 20 constructed at a total host-guest concentration of 2 mM, the concentration range at which the bis(peptidomimetic) 2 exists mainly as a monomer, so that the effect of host dimerization on the host-guest equilibrium could be eliminated. 1 H NMR titration experiments at a constant host concentration of 2 mM in CDCl 3 were also employed to determine their corresponding 1:1 association constant K a .…”

“…The structures of all compounds were confirmed by 1 H and 13 C NMR spectroscopy and mass spectrometry. 20,21 In particular, 1 H NMR signal assignments were facilitated by 2D ROSEY NMR spectroscopy. 20 The propensity of the bis(dipeptidomimetic) to selfassociate was studied by measuring their apparent molecular weight (MW app ) across a range of concentration (0.86-51 mM) in CHCl 3 at 30 °C using vapor pressure osmometry (VPO).…”

“…Branched peptides are excellent candidates for studying various biomolecular interactions due to their capabilities of multivalent binding. 1 By making use of the rich repertoire of amino acids and other artificial building blocks available for the construction of the peptide backbone and choosing a branching unit with suitable structural features, branched peptides or branched peptidomimetics have been demonstrated to show application in various areas such as heavy-metal detection, 2 water-oxidation catalysis, 3 peptide 4 and nucleotide 5 recognition, and as catalysts for biomolecular reactions. 6 Furthermore, branched peptides were also shown to exhibit different self-assembling properties that allow them to assemble into fibers, 7 vesicles, 8 and tubular constructs.…”

Molecular recognition of a branched peptide with HIV-1 Rev Response Element (RRE) RNA

“…Our laboratories have developed medium size branched peptides (BPs) that target RNA structures. 17 Their medium size (1000-2000 Da) is small enough to facilitate cell permeability but large enough to allow for increased surface area contact, making them more competitive against other RNA-binding ligands. 18 With one bead one compound (OBOC) peptide synthesis, diverse peptide libraries with a wide range of amino acids can be accessed, affording potential macromolecular interactions to increase selectivity and affinity.…”

Branched peptide with three histidines for the promotion of CuII binding in a wide pH range – complementary potentiometric, spectroscopic and electrochemical studies

“…11 The unique, three dimensional (3D) structure was also improved to be more effective in multiple antigen peptides (MAP), 12 in antibacterial 13 and in some therapeutic 14 agents. Expanding the eld of new, triple-arm peptides and their metal complex engineering can be crucial for the further development of those applications as well as, new enzyme mimicking centers, 15 some drugs, 16 radiopharmaceutics 17 or novel articial proteins.…”