Acquired Immune Deficiency Syndrome (AIDS) is a devastating infectious disease caused by the Human Immunodeficiency Virus type 1 (HIV-1). Enfuvirtide (T20) is the first HIV-1 fusion inhibitor for marketing, which plays an important role in AIDS treatment. However, in the clinical application process, T20 has several drawbacks, such as a high level of development of drug resistance, a short half-life <i>in vivo</i>, and rapid renal clearance, which severely limits the clinical application. Therefore, the development of novel fusion inhibitors to address T20 shortcomings has long been the research hotspot. Short peptides have a long half-life through modification and a high barrier to drug resistance, which is expected to solve the current fusion inhibitors dilemma. In this paper, we summarized six emerging R&D strategies for short peptide-based fusion inhibitors against HIV-1. We hope that this review will provide fresh insights into the development of novel fusion inhibitors, as well as ideas for other viral fusion inhibitor discoveries based on the common membrane fusion 6-HB core structure.

14 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Glycan-Modified Peptides for Dual Inhibition of Human Immunodeficiency Virus Entry into Dendritic Cells and T Cells

Q1 · MEDICINE

Article

Author: Li, Xuebing ; He, Lin ; Liu, Tong ; Xu, Mingyue ; Li, Mingli ; Cheng, Shuihong ; Ma, Liying ; Feng, Yong

Dendritic cells (DCs) play a crucial role in HIV-1 infection of CD4+ T cells. DC-SIGN, a lectin expressed on the surface of DCs, binds to the highly mannosylated viral membrane protein gp120 to capture HIV-1 virions and then transport them to target T cells. In this study, we modified peptide C34, an HIV-1 fusion inhibitor, at different sites using different sizes of the DC-SIGN-specific carbohydrates to provide dual-targeted HIV inhibition. The dual-target binding was confirmed by mechanistic studies. Pentamannose-modified C34 inhibited virus entry into both DC-SIGN+ 293T cells (52%-71% inhibition at 500 μM) and CD4+ TZM-b1 cells (EC₅₀ = 0.7-1.7 nM). One conjugate, NC-M5, showed an extended half-life relative to C34 in rats (T_1/2: 7.8 vs 1.02 h). These improvements in antiviral activity and pharmacokinetics have potential for HIV treatment and the development of dual-target inhibitors for pathogens that require the involvement of DC-SIGN for infection.

01 Feb 2024·Molecular Therapy

In vivo selection of anti-HIV-1 gene-modified human hematopoietic stem/progenitor cells to enhance engraftment and HIV-1 inhibition

Article

Author: Zakarian, Christina ; Kasahara, Noriyuki ; Brinkley, Alexander ; Lin, Samantha ; Parikh, Keval ; Shimizu, Saki ; Khamaikawin, Wannisa ; Zhang, Jian ; Pernet, Olivier ; An, Dong Sung ; Hacke, Katrin ; Guo, Qi

Hematopoietic stem/progenitor cell (HSPC)-based anti-HIV-1 gene therapy holds great promise to eradicate HIV-1 or to provide long-term remission through a continuous supply of anti-HIV-1 gene-modified cells without ongoing antiretroviral therapy. However, achieving sufficient engraftment levels of anti-HIV gene-modified HSPC to provide therapeutic efficacy has been a major limitation. Here, we report an in vivo selection strategy for anti-HIV-1 gene-modified HSPC by introducing 6-thioguanine (6TG) chemoresistance through knocking down hypoxanthine-guanine phosphoribosyl transferase (HPRT) expression using RNA interference (RNAi). We developed a lentiviral vector capable of co-expressing short hairpin RNA (shRNA) against HPRT alongside two anti-HIV-1 genes: shRNA targeting HIV-1 co-receptor CCR5 and a membrane-anchored HIV-1 fusion inhibitor, C46, for efficient in vivo selection of anti-HIV-1 gene-modified human HSPC. 6TG-mediated preconditioning and in vivo selection significantly enhanced engraftment of HPRT-knockdown anti-HIV-1 gene-modified cells (>2-fold, p < 0.0001) in humanized bone marrow/liver/thymus (huBLT) mice. Viral load was significantly reduced (>1 log fold, p < 0.001) in 6TG-treated HIV-1-infected huBLT mice compared to 6TG-untreated mice. We demonstrated that 6TG-mediated preconditioning and in vivo selection considerably improved engraftment of HPRT-knockdown anti-HIV-1 gene-modified HSPC and repopulation of anti-HIV-1 gene-modified hematopoietic cells in huBLT mice, allowing for efficient HIV-1 inhibition.

100 Deals associated with HIV-1 fusion Inhibitor(Kyoto University)

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Preclinical	Japan	Kyoto University	16 Jan 2008

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