Bifunctional backbone modified squaramide dipeptides as amyloid beta (Aß) aggregation inhibitors.

Alzheimer's disease (AD) is a devastating neurodegenerative condition with complex pathophysiology. Aggregated amyloid beta (Aß) peptide plaques and higher concentrations of bio-metals such as copper (Cu), zinc (Zn), and iron (Fe) are the most significant hallmarks of AD observed in the brains of AD patients. Therefore simultaneous inhibition of Aß peptide aggregation and reduction of metal stress may serve as an effective therapeutic approach for treating Alzheimer's disease. A series of bifunctional dipeptides bearing squaramide backbone were synthesized and investigated for their ability to chelate metal ions and prevent Aß peptide aggregation. Dipeptides with Valine (V) and Threonine (T) substitutions at the C-terminus exhibited preferential chelation with Cu(II), Zn(II), and Fe(III) metal ions in the presence of other metal ions. They were also found to inhibit the aggregation of Aß peptide in-vitro. A further molecular dynamics (MD) simulation study demonstrated that these two dipeptides interact with the Aß peptide in the hydrophobic core (KLVFF) region. Circular dichroism (CD) study revealed slight conformational change in the Aß peptide upon the interactions with dipeptides. Apart from metal chelation and inhibition of Aß peptide aggregation, the selected dipeptides were found to possess anti-oxidant properties. Therefore, the squaramide backbone-modified dipeptides may serve as an active bifunctional scaffold towards the development of new chemical entities for the treatment of Alzheimer's disease.

Microtubule stabilising peptides: new paradigm towards management of neuronal disorders.

Neuronal cells made of soma, axon, and dendrites are highly compartmentalized and possess a specialized transport system that can convey long-distance electrical signals for the cross-talk. The transport system is made up of microtubule (MT) polymers and MT-binding proteins. MTs play vital and diverse roles in various cellular processes. Therefore, defects and dysregulation of MTs and their binding proteins lead to many neurological disorders as exemplified by Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and many others. MT-stabilising agents (MSAs) altering the MT-associated protein connections have shown great potential for several neurodegenerative disorders. Peptides are an important class of molecules with high specificity, biocompatibility and are devoid of side effects. In the past, peptides have been explored in various neuronal disorders as therapeutics. Davunetide, a MT-stabilising octapeptide, has entered into phase II clinical trials for schizophrenia. Numerous examples of peptides emerging as MSAs reflect the emergence of a new paradigm for peptides which can be explored further as drug candidates for neuronal disorders. Although small molecule-based MSAs have been reviewed in the past, there is no systematic review in recent years focusing on peptides as MSAs apart from davunetide in 2013. Therefore, a systematic updated review on MT stabilising peptides may shed light on many hidden aspects and enable researchers to develop new therapies for diseases related to the CNS. In this review we have summarised the recent examples of peptides as MSAs.

Design and In-silico Screening of Peptide Nucleic Acid (PNA) Inspired Novel Pronucleotide Scaffolds Targeting COVID-19.

INTRODUCTION: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned into a pandemic, risking many human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive-sense single-stranded enveloped virus and closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced. METHODS: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes non-structural proteins like RNA-dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid-based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are at the advanced stage of clinical trials, including remdesivir. While performing a detailed investigation of the large set of nucleic acid-based drugs, we were surprised to find that the synthetic nucleic acid backbone has been explored very little or rare. RESULTS: We designed scaffolds derived from peptide nucleic acid (PNA) and subjected them to in- -silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess a similar binding affinity as remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates that compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 12,000mg/kg as opposed to remdesivir (LD50 =1000mg/kg). CONCLUSION: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid-derived compound can make it a leading scaffold to design, synthesize and evaluate many similar compounds for the treatment of COVID-19.

Design, synthesis and in-vitro evaluation of fluorinated triazoles as multi-target directed ligands for Alzheimer disease.

Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer's. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexafluorocarbinol containing triazoles to inhibit Amyloid ß aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid ß aggregation (IC50 of 4.6 µM) through selective binding with Amyloid ß at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu+2, Zn+2 and Fe+3) and scavenges ROS significantly. Due to the presence of hexafluorocarbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexafluorocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease.

Old Drugs with New Tricks: Paradigm in Drug Development Pipeline for Alzheimer's Disease.

The most common reason behind dementia is Alzheimer's disease (AD) and it is predicted to be the third life-threatening disease apart from stroke and cancer for the geriatric population. Till now, only four drugs are available on the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidence of molecular targets are the major hurdles for developing a new drug to treat AD. The rate of attrition of many advanced drugs at clinical stages makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repurposing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) consists of 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past, the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we have reviewed the clinical candidates for AD with emphasis on their development history, including molecular targets and the relevance of the target for AD.