Title

Rc-101, A Retrocyclin-1 Analogue With Enhanced Activity Against Primary Hiv Type 1 Isolates

Abstract

Rhesus macaques express three θ-defensins (RTDs 1-3), cyclic octadecapeptides with antiviral and lectin-like properties. Corresponding θ-defensin genes exist and are expressed in humans, but a signal sequence mutation prevents the formation of mature θ-defensin peptides. Retrocyclin-1 is a θ-defensin peptide whose precursor is encoded by human θ-defensin pseudogenes. It can protect human peripheral blood lymphocytes from infection by R5 and X4 strains of HIV-1, and provides a molecular template for designing novel antiviral agents. In this study, we used JC53-BL reporter cells to assess the activity of retrocyclin-1 (RC-100) and several analognes against primary HIV-1 isolates, including R5 and R5X4 strains of subtypes A-D, CRF-01_AE, and recombinants. Each analogue differed from retrocyclin-1 by a single amino acid substitution: Gly → Tyr in RC-106, RC-115, and RC-116, and Arg → Lys in RC-101. Although the modification in RC-101 was chemically conservative, this peptide was significantly more potent than retrocyclin-1 across the panel of primary isolates. We performed surface plasmon resonance binding studies, using recombinant gp120 and CD4 produced in insect cells. Although RC-100 and RC-101 bound gp120 LAV/IIIB with a Kd of 30-35 nM, they bound gp120 from CRF-01_AE strains (CM 235 and 93TH975.15) with K d values of 200-750 nM. Overall, our findings suggest that clade-related differences in gp120 glycosylation impact the ability of retrocyclin-1 to bind this viral glycoprotein, and modulate the peptides' ability to prevent HIV-1 infection. The performance of RC-101 suggests that additional "engineering" could further enhance the antiviral properties of θ-defensins.

Publication Date

11-1-2004

Publication Title

AIDS Research and Human Retroviruses

Volume

20

Issue

11

Number of Pages

1157-1165

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1089/aid.2004.20.1157

Socpus ID

9344221638 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/9344221638

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