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.

Background: Proprotein convertase subtilisin / Kexin type 9 (PCSK9) inhibitors are efficacious lipid-lowering agents. This drug is related to improving the prognosis of patients with cardiovascular disease (CVD). The pur-pose of this meta-analysis was to systematically analyze the safety and efficacy of PCSK9 inhibitors in all pub-lished randomized controlled trials (RCTs). Methods: As of October 25, 2021, we searched PubMed, EMBASE, MEDLINE, Cochrane Library and web of science. Results: From 684 articles, we included 11 trials for meta-analysis, including 52511 participants (26938 in the PCSK9 inhibitor group and 25573 in the control group). In terms of effectiveness, PCSK9 inhibitors reduced the risk of major adverse cardiovascular events(MACE) (OR=0. 89, 95% Cl: 0. 83-0. 95, P=0. 0009), but did not significantly reduce the risk of cardiovascular death (OR=0. 95, 95% Cl: 0. 84-1. 07, P=0. 38) or all-cause death (OR=0. 93, 95% Cl: 0. 85-1. 03, P=0. 18),In terms of safety, PCSK9 did not increase the risk of treatment-emergent adverse events (TEAE)(OR=0. 98, 95% Cl: 0. 94-1. 02, P=0. 28). Conclusion: PCSK9 inhibitors can significantly reduce the risk of MACE in patients with high cardiovascular risk, which is well tolerated, but the impact on the risk of death is unclear.

Background: Melanoma Inhibitory Activity 3 regulates the plasma level of LDL cholesterol. The c.3169+315G>A single-nucleotide polymorphism of the MIA3 gene has been reported to be associated with serum coronary artery disease (CAD). However, there have been no studies analyzing the association of this polymorphism with CAD in Iranian individuals with CAD.Objectives: Therefore, in the present study we have investigated the potential protective effect of the rs3008621 MIA3polymorphism in 188 subjects with and without CAD.Materials and Methods: Genotyping of the MIA3 gene was undertaken using Taq Man real-time PCR in all subjects. Anthropometric and biochemical features, including HDL, LDL, and TG were assessed in all subjects.Results: The CAD patients had significantly (P<0.05) higher BMI and significantly higher levels of TG, LDL, SBP, and DBP, while the level of HDL was lower compared to that of the control group. the MIA3 gene polymorphism was not associated with CAD in our population sample.Conclusions: The MIA3 polymorphism is unlikely to play an important role in CAD in the Iranian population. However, further studies are needed in a larger population to confirm this.