Abstract
The formation of amyloid-like fibrils is a central problem in biophysical chemistry and medicine. Fibril formation and their deposition in various tissues and organs are associated with many human diseases. Searching for molecules able to prevent the formation of fibrils is, therefore, necessary. In this work, we examined the potential of a cocrystal (SS3) of 3-((4-(3-isocyanobenzyl) piperazine-1-yl) methy) benzonitrile with 5-hydroxy isophthalic acid, to prevent fibrillation of human serum albumin. We found that the cocrystal strongly bound to human serum albumin (HSA) with association constant (Ka) of 5.8 ± 0.7 × 105 M−1. The SS3 binding was found to cause small alterations in both secondary and tertiary structure of the protein. Transmission electron microscopy showed that the cocrystal completely prevented the formation of worm-like protofibrils by HSA at SS3/HSA molar ratio of 1:1. The molecule was found to prevent the aggregation in a concentration dependent manner. It was also observed that most of protein in the presence of SS3 remained in soluble state and the secondary structure contained native-like α-helical structure. Therefore, we conclude that the cocrystal effectively prevented conversion of HSA into worm-like protofibril. These finding suggest that combination of molecules in the form of cocrystal or other stable combination could pave a way for the development of drugs against amyloidosis.
Communicated by Ramaswamy H. Sarma
Acknowledgements
B. A. for UGC-Faculty Recharge Program (UGC-FRP), UGC, Govt. of India for awarding UGC Assistant Professor position and SAM for ICM-SRF position awarded by Indian Council of Medical Research (ICMR), Govt. of India, New Delhi.
Disclosure statement
Sadiya Shabbir, Mohd Muslim, Shivani A. Muthu, Raghuvir R. S. Pissurlenkar, Shaista Fatima, Arif Ali, Aiman Ahmad, Musheer Ahmad and Basir Ahmad declare that they have no conflict of interests.
Compliance with ethics guidelines
This article does not contain any studies with human or animal subjects performed by the any of the authors.