ABSTRACT
HIV-1 reverse transcriptase (RT) inhibitors are fundamental to the discovery and development of anti-HIV drugs. Their main target is RT, and only a tiny number of them can bind to viral RNA. In this paper, five new Zn(II) porphyrin compounds were developed with different characters. ZnTPP4 has both the appearance and the functions of a scorpion with a rigid tail and stinger to selectively hunt HIV-1 TAR RNA based on the molecular recognition of hydrogen bonds, a fierce chelicera to bite RNA by metal coordination, mighty pedipalps to grasp the bound RNA by supramolecular inclusion, and a broad body maintaining the configuration of each functional area so that they can cooperate with each other and providing accommodation space for the bound RNA. This tetrafunctional Zn(II) porphyrin is relatively nontoxic to normal cells and can produce sensitive responses for RNA. Moreover, this work offers practical construction methodologies for medication of AIDS and other diseases closely related to RT like EBOV and SARS-CoV-2.
Subject(s)
COVID-19 , HIV-1 , Metalloporphyrins , Reverse Transcriptase Inhibitors , HIV Reverse Transcriptase/antagonists & inhibitors , Humans , Metalloporphyrins/pharmacology , RNA, Viral , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , SARS-CoV-2ABSTRACT
Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 µM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.