New perspectives on the use of nucleic acids in pharmacological applications: inhibitory action of extracellular self-DNA in biological systems Stefano Mazzoleni • Fabrizio Cartenı ` • Giuliano Bonanomi • Guido Incerti • Maria Luisa Chiusano • Pasquale Termolino • Antonello Migliozzi • Mauro Senatore • Francesco Giannino • Max Rietkerk • Antonio Risitano • Virginia Lanzotti Received: 26 April 2014 / Accepted: 27 October 2014 / Published online: 2 November 2014 Ó Springer Science+Business Media Dordrecht 2014 Abstract The research for new products against pathogens, parasites and infesting species, in both agriculture and medicine, implies huge and increasing scientific, industrial and economic efforts. Traditional approaches are based on random screening procedures searching for bioactive compounds. However, the success of such methodologies in most cases has been strongly limited by side-effects of the potential new drugs, especially toxicity and pharmacological resis- tance. The use of nucleic acids in drug development has been introduced searching for target-specific effect. In addition, a recent discovery revealed that randomly fragmented extracellular self-DNA may act as highly species-specific inhibitory product for dif- ferent species, suggesting an unprecedented use of DNA for biological control. On this base, a new scenario of pharmacological applications is discussed. Keywords Drug discovery Á Random screening Á Combinatorial synthesis Á Nucleosides analogues Á Conspecific DNA Á Antisense oligonucleotides Á Autotoxicity Introduction The goal of the pharmaceutical research is the discovery of new drugs with a specific and selective action against pathogens, parasites and infesting species minimizing or, even better, eliminating the side-effects. Traditional approaches are based on random screening procedures searching for bioactive compounds from different sources (Koehn and Carter 2005; Newman and Cragg 2007; Swinney and Anthony 2011). However, the development of poten- tial new drugs in most cases has been limited by side- effects such as toxicity and induction of resistance (Butler 2008). Despite the major and increasing scientific, economic and industrial efforts on research of new products in both agriculture and medicine, the rate of approval is decreased in recent years (Kaitin and DiMasi 2011; Morgan et al. 2011). The recent discovery of the toxic effects of nucleic acids on S. Mazzoleni (&) Á F. Cartenı ` Á G. Bonanomi Á G. Incerti Á M. L. Chiusano Á A. Migliozzi Á M. Senatore Á F. Giannino Á V. Lanzotti Dipartimento di Agraria, University of Naples Federico II, Via Universita ` 100, 80055 Portici, NA, Italy e-mail: stefano.mazzoleni@unina.it P. Termolino CNR-IGV, Istituto di Genetica Vegetale, Via Universita ` 133, 80055 Portici, NA, Italy M. Rietkerk Department of Environmental Sciences, Utrecht University, PO Box 80115, 3508 TC Utrecht, The Netherlands A. Risitano Dipartimento di Medicina clinica e Chirurgia, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy 123 Phytochem Rev (2014) 13:937–946 DOI 10.1007/s11101-014-9386-9