Galectin approach to lower covid transmission - Drug Development for clinical use

BackgroundSARS-CoV-2 vaccines play an important role in reducing disease severity, hospitalization, and death, although they failed to prevent the transmission of SARS-CoV-2 variants. Therefore, an effective inhibitor of galectin-3 (Gal-3) could be used to treat and prevent transmission of COVID-19. ProLectin-M (PL-M), a Gal-3 antagonist, has been shown to interact with Gal-3 and thus prevent cellular entry of SARS-CoV-2 in previous studies. AimThe present study aimed to further evaluate the therapeutic effect of PL-M tablets in 34 subjects with COVID-19 disease, in addition to determining the mechanism of PL-M in preventing SARS-CoV-2 cell entry by NMR studies. MethodsThe efficacy of PL-M was evaluated in a randomized, double-blind, placebo-controlled clinical study in patients with mild to moderately severe COVID-19. Primary endpoints included changes in absolute RT-PCR Ct values of the nucleocapsid and open reading frame (ORF) genes from baseline to days 3 and 7. The incidence of adverse events, changes in blood biochemistry, inflammatory biomarkers, and levels of antibodies against COVID-19 were also evaluated as part of the safety evaluation. In vitro 1H-15N HSQC NMR spectroscopy studies were also performed to determine the interactions of PL-M with Gal-3 and the S1 spike protein of SARS-CoV-2. ResultsPL-M treatment significantly (p = 0.001) increased RT-PCR cycle counts for N and ORF genes on days 3 (Ct values 32.09 and 30.69 {+/-} 3.38, respectively) and 7 (Ct values 34.91 {+/-} 0.39 and 34.85 {+/-} 0.61, respectively) compared to placebo. On day 3, 14 subjects in the PL-M group had cycle counts for the N gene above the cut-off of 29 (target cycle count 29), while on day 7 all subjects had cycle counts above the cut-off. Ct values in placebo subjects were consistently less than 29, and no placebo subjects were RT-PCR negative, until day 7. 1H-15N HSQC NMR spectroscopy revealed that PL-M specifically binds Gal-3 in the same way as the structurally similar NTD of the SARS-CoV-2 S1 subunit. ConclusionPL-M is safe and effective for clinical use in reducing viral load and promoting rapid viral clearance in COVID-19 patients by inhibiting SARS-CoV-2 entry into cells through inhibition of Gal-3.