Furin is a serine protease that takes part in the processing and activation of the host cell pre-proteins. The enzyme also plays an important role in the activation of several viruses, such as the SARS-CoV-2 virus, the causative agent of COVID-19 disease which inflicted a high rate of mortality. Unlike other viral enzymes, furin has a constant sequence and active site characteristics and seems to be a better target for drug design for COVID-19 treatment. Considering furin active site as receptor and some approved drugs as ligands, we have carried out docking experiments in HEX software to pick up those which are capable of binding furin active site with high affinity. The tested drugs were chosen from different classes, including antivirals, antibiotics, and anti-protozoa/anti-parasites with suspected beneficial effects on COVID-19. Our docking experiments show that saquinavir, nelfinavir, and atazanavir with respective cumulative inhibitory effects of 2.52, 2.16, and 2.13, respectively are the best candidates for furin inhibition. Clarithromycin, niclosamide, and erythromycin show cumulative inhibitory indices of 1.97, 1.90, and 1.84, respectively. Considering the lower side effects of clarithromycin, niclosamide, and erythromycin in contrast to the antivirals such as saquinavir, nelfinavir, and atazanavir, we suggest the formers as prophylaxes and even at severe states of COVID-19 as adjuvant therapy.

Furin is a Ca2+ -dependent serine protease which cleaves proprotein substrates at the Arg-Xaa-(Lys/Arg)-Arg ↓ site to generate biologically active proteins. Furin’s critical role in many cellular events associated with health disorders such as HIV, SARS, anthrax, and influenza as well as cancer has made inhibitors of this enzyme as therapeutic targets. To this date, the most potent inhibitor of furin is the bioengineered serpin (serine protease inhibitors) protein namely α -PDX. It was already demonstrated that the reactive site loop (RSL) of all serpins are prime interactive domains responsible for their protease inhibitory function. Therefore, the objective of the present study was to develop small peptides with the RSL structure of serpin α -PDX, as inhibitors of furin activity. Fifteen peptides were designed from reactive site loop structure of α-PDX (sequences 367-394) with different mutations in this site, and were synthesized using a solid-phase peptide synthesizer, and characterized by MALDI-tof mass spectrometry and amino acid analysis. The inhibitory effects of the designed peptides against furin activity were evaluated by spectroflourometry using QVEGF-C [Abz-QVHSIIRRßSLP-Y(NO2)-A-CONH2, Abz = 2-amino benzoic acid and Y(NO2) = 3-nitro tyrosine] as substrate. The results showed that all of the designed peptides inhibit furin activity with different efficacies in a time and concentration dependent pattern. Peptides containing His or straight alkyl side chain amino acids in positions P2, P3, P6 and P8 have higher efficacy for blocking furin activity in comparison with peptides containing Arg or Lys in that position. The study further revealed that the peptides inactivate furin in a slow tight binding pattern. Our study provides an alternate strategy for development of efficient peptide-based inhibitors of proprotein convertases such as furin.