What are Fusion Inhibitors?

Fusion inhibitors, which are commonly used anti-HIV-1 drugs, target N-HR or C-HR, block the combination of the two, and prevent the virus from entering the host cell.

Definition of fusion inhibitor

Fusion inhibitors, which are commonly used anti-HIV-1 drugs, target N-HR or C-HR, block the combination of the two, and prevent the virus from entering the host cell.

Classification of fusion inhibitors

1.T-20 Fusion inhibitor 1. Fusion inhibitor T-20

In March 2003, the HIV-1 peptide fusion inhibitor enfuvirtide (Fuzeon), also known as T-20, was jointly developed by Roche of Switzerland and Trimeris of the United States. Confirmation of membrane glycoprotein gp41 as an effective target for anti-HIV-1 drugs.

2HIV-1 Fusion inhibitor 2 peptide HIV-1 fusion inhibitor

2.1 C peptide fusion inhibitors

C-peptides are synthetic peptides derived from HR2. They target gp41 NHR trimer (N-trimer) and are currently the most researched and most promising drug development HIV-1 fusion inhibitors. In addition to the listed T-20, there are currently many C-peptide compounds in different clinical research stages.

2.2 N-peptide fusion inhibitors

N-peptides are the earliest peptides found to inhibit HIV-1 fusion activity. They are sequences derived from gp41 HR1. For example, DP-107 is the first polypeptide to be found to have anti-fusion activity. There are two possible mechanisms of action of N-peptide: one is to bind to HR2 to inhibit 6-HB formation; the other is to form heterotrimers with HR1 to destroy its own N-trimer formation. Although N-peptides show some activity to inhibit HIV fusion, compared to C-peptides, their activity is very low, such as DP-107 is 1,000 times lower than T-20. In addition, a single N-peptide has poor solubility and is easy to aggregate itself. Therefore, the research on N-peptide mainly focuses on overcoming the above-mentioned shortcomings.

2.3 Fusion inhibitors targeting the gp41 fusion peptide (FP)

Fusion peptide refers to a highly hydrophobic region composed of about 23 amino acids at the N-terminus of the gp41 transmembrane glycoprotein. It plays a key role in the fusion process of HIV-1 envelope and host cell membrane. At the initial stage of membrane fusion, the HIV-1 envelope glycoprotein surface subunit gp120 binds to the CD4 receptor and co-receptor on the surface of target cells, respectively, causing the conformation of gp41 to change. Among them, it is the first step to start the fusion process. Munch et al. [38] separated and identified tens of thousands of liters of hemodialysate, and found a natural component that can block HIV-1 virus infection from more than one million peptide sequences, and named it virus inhibitory peptide (VIRIP). VIRIP consists of 20 natural amino acids. By specifically binding to FP, VIRIP blocks the insertion of FP into the cell membrane, thereby inhibiting membrane fusion. Through structural modification and modification of VIRIP, the researchers designed and synthesized more than 600 analogs, and found several peptide sequences containing disulfide bonds. The activity was increased by two orders of magnitude compared to VIRIP and reached the nanomolar level. At the same time, experimental data show that VIRIP can inhibit more than 60 HIV strains, including virus strains that have developed resistance to clinical drugs, without cytotoxicity. Further research shows that the FP region is highly conserved, and the chance of HIV-1 virus producing resistance mutations to VIRIP is very small. Therefore, VIRIP analogs have good drug-making properties, which brings hope for the development of new anti-AIDS drugs.

2.4 Unnatural amino acid modified HIV-1 fusion inhibitory polypeptide

D-peptide (peptide composed of D-type amino acids) can inhibit protease degradation and has potential oral bioavailability. Applying the mirror phage display method, Eckert et al. Screened a large (> 109) peptide library and found a series of peptides with moderate inhibitory activity (IC50 value of about 10 mol N-trimer's hydrophobic pocket region, indicating that the simple pocket region can also be used as a target for small molecule fusion inhibitors.

Development prospects of fusion inhibitors

Sifuvirtide, an HIV membrane fusion inhibitor independently developed by China, has successfully completed the phase IIb clinical trial, and its curative effect is very significant.
Sifuvirtide belongs to the national class one innovative patented drug and was independently developed by Tianjin Fusu Biological Company. Based on the spatial structure of the HIV membrane fusion protein gp41, Fusu Biological Co., Ltd. has newly designed and synthesized a new generation of membrane fusion inhibitors. It has been granted patents in China, the United States and Europe, and has published more than 10 related majors in international magazines. article.
According to reports, Fusu Biological has completed pre-clinical studies of Sifuvirtide and Phase a, b, a and b clinical studies. All clinical studies have been conducted in accordance with the requirements of the National Pharmaceutical Clinical Trial Management Regulation (GCP), with a total of more than 200 Volunteers and infected persons participated in clinical studies. The results of the study show that sifuvirtide is safe and well tolerated; the single-agent effect of 20mg sifuvirtide once a day is equivalent to T20, a similarly marketed drug in the United States, twice daily. Phase IIb trial results show that after 24 weeks of combined treatment, Sifuvirtide can significantly improve the antiviral effect. Compared with traditional antiviral drugs, Sifuvirtide can reduce HIV load to undetectable. Increased the level by 59% and increased the increase rate of CD4 cell count by 89%. The incidence of sifuvirtide injection site reactions was 7%, much lower than 98% of T20.