Sfn0011: a sflt01-based novel tri-specific molecule with antiangiogenic activity

Hamid Latifi-navid,1 Zahra-soheila soheili,2,* Mehdi sadeghi,3 Shahram samiei,4 Ehsan ranaei pirmardan,5 Seyed shahriar arab,6

1. National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
2. National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
3. National Institute of Genetic Engineering and Biotechnology, Tehran, Iran; School of Biological Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran.
4. Blood Transfusion Research Centre High Institute for Research and Education in Transfusion, Medicine, Tehran, Iran
5. Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
6. Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

Abstract

Introduction

Age-related macular degeneration (amd) is the leading cause of blindness among elderly patients in developed countries. since vegf plays a key role in the pathogenesis of choroidal neovascularization )cnv(, targeting vegf has been an attractive strategy in the treatment of cnv, initiating extensive research in recent years. however, experimental and clinical experience show that the efficacy of anti-vegf monotherapy is limited due to overlapping and compensatory alternative angiogenic pathways which provide escape mechanisms. indeed, anti-vegf monotherapy only blocks one the most known pathway of pathological angiogenesis and other angiogenic factors may lead to disease progression. therefore, the complimentary combination of factors that inhibit alternative mechanisms of blood vessel formation may improve clinical benefit for patients. sflt01 is a novel fusion protein that consists of vegf/plgf (placental growth factor) binding domain of human vegfr1/flt-1 (hvegfr1) fused to the fc fragment of human igg(1) through a polyglycine linker. this molecule has the capacity of binding to human vegf (hvegf), human plgf (hplgf), mouse vegf (mvegf) and mouse plgf (mplgf).

Methods

We investigated sflt01 molecule structural components with bioinformatics tools and achieved to its amino acid and nucleotide sequences. we assembled these sequences and then included the nucleotide sequence of single-chain variable fragment (scfv) to sflt01ʹs. indeed we designed a sflt01-based novel tri-specific molecule (sfn0011) that targets vegf-a, plgf and a third party of angiogenic factors that exerts important roles in formation of new blood vessels. then we analyzed the secondary and tertiary structures of the tri-specific molecule with swiss-model and i-tasser. by choosing the best models, protein-protein docking with cluspro was performed.

Results

Docking results showed the capacity sfn0011 to bind with vegf-a, plgf and the third party angiogenic factor in predefined areas.

Conclusion

We propose that targeting several angiogenic pathways by sfn0011 may be a promise for next generation antiangiogenic therapeutic for age related macular degeneration.

Keywords

Sfn0011 sflt01 age-related macular degeneration vegf