Oral Presentation 5th Modern Solid Phase Peptide Synthesis Symposium 2015

Intracellular target-specific activities of proteomimetic bioportides (#17)

John Howl 1 , Sarah Jones 1
  1. University of Wolverhampton, Wolverhampton, United Kingdom

Cell penetrating peptide (CPP) technologies represent a viable strategy to modulate the activities of intracellular proteins that are often intractable to more conventional biological agents. In particular, the cationic helical domains of proteins have proven to be a reliable source of proteomimetic bioportides, cell penetrant sequences that control intracellular protein function by a predominant dominant negative mechanism. Arginine-rich helical protein sequences are a common source of bioportides, a fact that in part reflects the increased propensity of arginine within the molecular interfaces that facilitate protein-protein interactions (PPIs). Thus, our current endeavours broadly encompass the design, synthesis and evaluation of polycationic bioportides within key signalling proteins that control apoptosis, tumour angiogenesis and the pathophysiology of Parkinson’s disease [1]. Such studies reveal that many bioportides are able to selectively target intracellular proteins and so manipulate cellular physiology and biochemistry. 

We have recently demonstrated that selected CPPs act as novel site-specific intracellular delivery vectors for applications with mammalian spermatozoa [2]. Hence, CPP technologies could be utilised to deliver bioactive cargoes into discrete intracellular compartments of human sperm. Such findings are significant since mature spermatozoa lack the endocytotic capacity of somatic cell types. Moreover, as human sperm do not translate their haploid genome, unique PPI networks are essential for the control of fundamental processes such as the acquisition of motility which correlates with reproductive capacity. We have, therefore, recently utilised bioportides to target PPIs and so manipulate key aspects of  sperm physiology including calcium signalling [3]. Our major objective is to further identify and refine related bioportide technologies to selectively modulate sperm-specific PPI networks in a clinical setting. The development of such innovative technologies could potentially rectify male infertility and also provide a novel approach towards male contraception.

  1. Howl, J. & Jones S. (2015) Insights into the molecular mechanisms of action of bioportides: a strategy to target protein-protein-interactions. Expert Rev. Mol. Med. doi.org/10.1017/erm.2014.24 Vol 17, e1.
  2. Jones, S., Lukanowska, M., Suhorutsenko, J., Oxenham, S., Barratt, C., Publicover, S., Copolovici D.M., Langel, Ü. & Howl, J. (2013) Intracellular translocation and differential accumulation of cell penetrating peptides in bovine spermatozoa: Evaluation of efficient delivery vectors that do not compromise human sperm motility. Hum. Reprod. 28, 1874-1889.
  3. Morris, J., Jones, S., Lukanowska, M., Howl, J. & Publicover, S. (2015) Cell penetrating peptides, targeting the regulation of store-operated channels, slow decay of the progesterone-induced [Ca2+]i signal in human sperm. Mol. Hum. Reprod. 21, 563-570.