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.
Subject(s)
Hydroxy Acids , Serum Albumin , Amyloid , Humans , Nitriles , Phthalic Acids , PiperazineABSTRACT
Pakistan is being hit by communicable and noncommunicable diseases over time. Among these, tickborne viral disease, Crimean-Congo hemorrhagic fever (CCHF) is one of the most fatal infections. Rapid climate change aroused by industrial, occupational, and agricultural activities to support ever-growing human population has been considered the single most causative basis for emergence or re-emergence of CCHF in Pakistan, where it has biannual peaks between the months of March-May and August-October. Many factors, including poor sanitation at farms, villages, and cities, unhygienic transportation and slaughter of animals at numerous sites within a city, inefficient tick-control programs, post-slaughter piles of animal remains other than meat, nomadic lifestyle, and lack of trained animal and human healthcare staff, are contributing to the spread of CCHF. Pakistan has confirmed cases of CCHF in almost every province: Sindh (Karachi), Punjab (Faisalabad, Multan, and Rawalpindi), Balochistan (Quetta) and Khyber Pakhtunkhwa (Peshawar). The root cause behind the spread of CCHF in Pakistan seems to be the absence of an effective disease surveillance system in the human as well as the animal populations. Most of the time, CCHF cases are not diagnosed, and if they are diagnosed they are not reported. If these cases are reported, there are not enough effective measures by the relevant provincial and district authorities. There is a need to educate the general public, farmers, and healthcare workers about the causes, transmission, and dangers of CCHF. An immediate plan for the implementation of a surveillance system, standard preventive measures, early detection, proper treatment, and timely response is urgently needed. Without such a plan, the accumulation of factors responsible for the sudden outbreak of CCHF may pose a serious threat to humans and animals in different geographical regions of the country.
