Abstract
Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracytoplasmic sperm injection (ICSI). However, PTX is reported to induce premature acrosome reaction (AR) and, exert toxic effects on oocyte function and early embryo development. Additionally, in vitro binding studies as well as computational binding free energy (ΔGbind) suggest that PTX exhibits weak binding to sperm PDEs, indicating room for improvement. Aiming to reduce the adverse effects and to enhance the sperm motility, we designed and studied PTX analogues. Using structure-guided in silico approach and by considering the physico-chemical properties of the binding pocket of the PDEs, designed analogues of PTX. In silico assessments indicated that PTX analogues bind more tightly to PDEs and form stable complexes. Particularly, ex vivo evaluation of sperm treated with one of the PTX analogues (PTXm-1), showed comparable beneficial effect at much lower concentration—slower AR, higher DNA integrity and extended longevity of spermatozoa and superior embryo quality. PTXm-1 is proposed to be a better pharmacological agent for ART than PTX for sperm function enhancement.
Highlights
Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracytoplasmic sperm injection (ICSI)
For assisted reproductive technologies (ART), where the frozen-thawed semen and testicular spermatozoa samples are used for infertility treatment, motility enhancement can be b eneficial[13]
molecular dynamics (MD) simulation and computational ΔGbind analyses of PTX analogues and a comparison with parent PTX molecule indicated that redesigned phosphodiesterase inhibitors (PDEIs) are more potent than PTX
Summary
Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracytoplasmic sperm injection (ICSI). Abbreviations AC Adenylyl cyclase AR Acrosome reaction ART Assisted reproductive technologies cAMP Cyclic adenosine monophosphate ΔGbind Free energy of binding ICSI Intracytoplasmic sperm injection ITC Isothermal titration calorimetry bt.iith.ac.in. Identification of factors influencing sperm motility in vitro[9,10,11,12], has immensely benefited assisted conception methods such as intrauterine insemination (IUI), in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). For assisted reproductive technologies (ART), where the frozen-thawed semen and testicular spermatozoa samples are used for infertility treatment, motility enhancement can be b eneficial[13]. The level of cAMP is tightly and dynamically regulated by two major enzymes, the adenylyl cyclases (ACs) and the phosphodiesterases (PDEs), which catalyze, respectively, the synthesis and degradation of c AMP16
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