Remodeling of gp41-C34 Peptide Leads to Highly Effective Inhibitors of the Fusion of HIV-1 with Target Cells We thank Dr. Terrence R. Burke, Jr., NCI, NIH, Frederick, MD 21702-1201, for proofreading the manuscript and providing useful comments. This research was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, the Japan Society for the Promotion of Science, and the Japan Health Science Foundation.

Abstract

Membran derZielzelle HIV-1-Membran veränderte gp41-Peptide zur Verschmelzung nicht in der Lage Fusion zwischen HIV-1 und Zelle zur Verschmelzung fähig Kristall des Komplexes, der aus roten und blauen Stäbchen besteht schematische Darstellung von HIV-1 Die Verschmelzung von HIV-1 mit Zielzellen wird durch die Insertion von gp41 in die Zellmembran vermittelt, an die sich die Bildung eines Sechs-Helix-Bündels anschließt. Künstlich veränderte gp41-Peptide können die Bildung des Sechs-Helix-Bündels inhibieren; sie zeigen eine äußerst hohe anti-HIV-1-Aktivität und sind sehr gut wasserlöslich.Mehr dazu erfahren Sie auf den folgenden Seiten.

Chemoenzymatic Synthesis of HIV‐1 gp41 Glycopeptides: Effects of Glycosylation on the Anti‐HIV Activity and α‐Helix Bundle‐Forming Ability of Peptide C34

“…The oligosaccharide donor Man 9 GlcNAc 2 Asn that was used for transglycosylation was prepared from soybean flour following a modified procedure 15. We observed that, as in the case of C34,5, 8, 16 GlcNAc‐C34 demonstrated a very low solubility in aqueous media. An initial attempt to perform the enzymatic transglycosylation in phosphate buffer failed to give any transglycosylation product due to the low concentration of the acceptor GlcNAc‐C34 in the reaction media.…”

“…First, LacNAc‐C34 and M9‐C34 have a much better solubility under physiological conditions than C34, which overcomes a major drawback encountered for the clinical use of C34 5. 8, 16 Secondly, because of the general protective effect of glycosylation, the glycopeptides could be more resistant to protease digestion in vivo than C34, although the overall in vivo efficiency of glyco‐C34 and C34 is yet to be tested in animal models.…”

Development of Peptide and Small‐Molecule HIV‐1 Fusion Inhibitors that Target gp41

“…A new generation of peptide fusion inhibitors was developed by engineering T20 and C34 sequences to increase their in vivo stability and NHR binding affinity, and to overcome T20 resistance. It is well accepted that increasing the helical content of peptide fusion inhibitors will also improve their anti‐HIV‐1 potency by increasing their binding affinity for NHR as well as their in vivo stability 39. In a 6HB, C‐peptides interact with the NHR at its a and d positions in the heptad registry, which is considered important for molecular recognition between CHR and NHR, while residues at the b , c , f , and g positions are solvent‐exposed, and thus not considered important for the gp41 NHR–CHR interaction 22.…”

Inhibition of HIV‐1 Fusion by Hydrogen‐Bond‐Surrogate‐Based α Helices

“…The limited solubility of short C‐peptides in aqueous solution has been proposed as a key reason for their inactivity 19. To improve the solubility and helicity of constrained C‐peptides, we incorporated charged residues at positions not expected to be involved in binding to IZN17, based on the work of Otaka, Fujii, and co‐workers 19. HBS α helix 3 is the shortest peptide designed to contain the Trp/Trp/Ile motif necessary for binding.…”