Nitin Patil

Nitin Patil
Monash University (Australia) · Department of Microbiology

Doctor of Philosophy

About

37
Publications
9,701
Reads
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534
Citations
Introduction
Inspired by cellular mechanisms, our research utilizes a multidisciplinary approach to develop new therapeutics. Our main goal is to develop biomolecules such as oligonucleotides and peptides to enhance their therapeutic properties for human medicine. Our research also focuses on creating new chemistry tools for the selective modification of oligonucleotides and peptides, for efficient drug delivery into specific cells.
Additional affiliations
January 2019 - present
Monash University (Australia)
Position
  • Fellow
Description
  • Research Interests: 1) Polymyxin based antibiotic drug development 2) Peptide Nucleic Acids (PNAs) as antisense antibiotics 3) Backbone modified antisense oligonucleotides
February 2018 - present
Monash University (Australia)
Position
  • Fellow
Description
  • Research Interests: 1) Polymyxin based antibiotic drug development 2) Peptide Nucleic Acids (PNAs) as antisense antibiotics
November 2017 - present
Monash University (Australia)
Position
  • Research Associate
Description
  • Dru discovery and development of novel polymyxins against Gram-negative 'superbugs'
Education
January 2013 - July 2016
University of Melbourne
Field of study
  • Peptide Chemistry
July 2006 - April 2008
Narsee Monjee Institute of Management Studies
Field of study
  • Pharmaceutical Chemistry
July 2002 - May 2006
Savitribai Phule Pune University
Field of study
  • Pharmacy

Publications

Publications (37)
Article
Multidrug-resistant Gram-negative bacteria seriously threaten modern medicine due to the lack of efficacious therapeutic options. Their outer membrane (OM) is an essential protective fortress to exclude many antibiotics. Unfortunately, current structural biology methods are not able to resolve the membrane structure and it is difficult to examine t...
Article
Full-text available
The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colisti...
Article
Full-text available
Peptide-Peptide Nucleic Acid (PNA) conjugates targeting essential bacterial genes have shown significant potential in developing novel antisense antimicrobials. The majority of efforts in this area are focused on identifying different PNA targets and the selection of peptides to deliver the peptide-PNA conjugates to Gram-negative bacteria. Notably,...
Article
Full-text available
Multidrug-resistant Gram-negative bacteria represent a major medical challenge worldwide. New antibiotics are desperately required with 'old' polymyxins often being the only available therapeutic option. Here, we systematically investigated the structure-activity relationship (SAR) of polymyxins using a quantitative lipidomics-informed outer membra...
Article
Full-text available
The rapid generation and modification of macrocyclic peptides in medicinal chemistry is an ever-growing area that can present various synthetic challenges. The reaction between N-terminal cysteine and 2-cyanoisonicotinamide is a new biocompatible click reaction that allows rapid access to macrocyclic peptides. Importantly, 2-cyanoisonicotinamide ca...
Article
Oligonucleotide-based agents are versatile biomolecules that modulate gene expression. The last decade has seen the emergence of oligonucleotide-based tools for biochemical investigations. Importantly, several oligonucleotide-based drugs and vaccines are currently used for various therapeutic applications ranging from anti-inflammatory and anti-vir...
Article
Background: MDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative 'superbugs', including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between...
Article
Full-text available
The octapeptins are lipopeptide antibiotics that are structurally similar to polymyxins yet retain activity against polymyxin-resistant Gram-negative pathogens, suggesting they might be used to treat recalcitrant infections. However, the basis of their unique activity is unclear due to the difficulty in generating high-resolution experimental data...
Article
Full-text available
Multidrug‐resistant Acinetobacter baumannii is a top‐priority pathogen globally and polymyxins are a last‐line therapy. Polymyxin dependence in A. baumannii (i.e., nonculturable on agar without polymyxins) is a unique and highly‐resistant phenotype with a significant potential to cause treatment failure in patients. The present study discovers that...
Article
Full-text available
In article number 2000704, Jian Li and co‐workers elucidate the novel mechanism of dependent resistance to the last‐line polymyxins in a high‐priority “superbug” Acinetobacter baumannii. Polymyxindependent resistance cannot be detected by conventional microbiological diagnosis due to the lack of growth on normal agar plates. These polymyxin‐depende...
Article
Surfaces are abundant in living systems, such as in the form of cellular membranes, and govern many biological processes. In this study, the adsorption of the amyloidogenic model peptides GNNQQNY, NNFGAIL, and VQIVYK as well as the amyloid-forming antimicrobial peptide uperin 3.5 (U3.5) were studied at low concentrations (100 μM) to different surfa...
Article
Many peptides aggregate into insoluble β-sheet rich amyloid fibrils. Some of these aggregation processes are linked to age-related diseases, such as Alzheimer’s disease and type 2 diabetes. Here, we show that the secondary structure of the peptide uperin 3.5 directs the kinetics and mechanism of amyloid fibrillar aggregation. Uperin 3.5 variants we...
Article
Structure‐activity relationship studies are a highly time‐consuming aspect of peptide‐based drug development, particularly in the assembly of disulfide‐rich peptides which often requires multiple synthetic steps and purifications. Therefore, it is vital to develop rapid and efficient chemical methods to readily access the desired peptides. We have...
Article
Antisense oligonucleotides (ASO)-based drugs are emerging with great potential as therapeutic compounds for diseases with unmet medical needs. However, for ASOs to be effective as clinical entities, they should reach their intracellular RNA and DNA targets at pharmacologically relevant concentrations. Over the past decades various covalently attach...
Article
Amyloid fibrils are highly ordered, β-sheet rich forms of aggregated peptides and proteins that are associated with a variety of pathological human disorders, including Alzheimer's and Parkinson's diseases. Amyloid fibril-forming peptides may be functionally related to antimicrobial peptides, despite differing significantly in sequence and structur...
Article
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality worldwide, is characterised by the homozygous loss of the survival motor neuron 1 (SMN1) gene. The consequent degeneration of spinal motor neurons and progressive atrophy of voluntary muscle groups results in paralysis and eventually premature infantile death. Humans posse...
Conference Paper
Insulin-like peptide 5 (INSL5) is a member of the insulin/relaxin family of peptides. The colonic expression of INSL5 is largely restricted to the L-type enteroendocrine cell population. Immunostaining of murine primary colonic cultures and of colonic sections from human revealed cells co-stained for INSL5 together with GLP1 and PYY highlighting L-...
Article
The human relaxin peptide family consists of seven cystine-rich peptides, four of which are known to signal through relaxin family peptide receptors, RXFP1-4. As these peptides play a vital role physiologically and in various diseases, they are of considerable importance for drug discovery and development. Detailed structure-activity relationship (...
Article
The relaxin family peptide receptor 4 (RXFP4) is a G protein-coupled receptor (GPCR) expressed in the colorectum with emerging roles in metabolism and appetite regulation. It is activated by its cognate ligand insulin-like peptide 5 (INSL5) that is expressed in enteroendocrine L cells in the gut. Whether other evolutionarily related peptides such a...
Article
Despite recent advances in the treatment of diabetes mellitus, storage of insulin formulations at 4 °C is still necessary to minimize chemical degradation. This is problematic in tropical regions where reliable refrigeration is not ubiquitous. Some degradation byproducts are caused by disulfide shuffling of cystine that leads to covalently bonded o...
Article
Full-text available
Despite recent advances in the treatment of diabetes mellitus, storage of insulin formulations at 4 °C is still necessary to minimize chemical degradation. This is problematic in tropical regions where reliable refrigeration is not ubiquitous. Some degradation byproducts are caused by disulfide shuffling of cystine that leads to covalently bonded o...
Article
Cystine-rich heterodimeric peptides or proteins (e.g. insulin) are attractive drug targets. However, their chemical assembly and correct folding is complex, time-consuming, and often low yielding. In their Communication (10.1002/anie.201604733) N. A. Patil, M. A. Hossain, and co-workers describe a novel strategy in which two peptide chains are sequ...
Article
Cystin-reiche heterodimere Peptide oder Protein (z. B. Insulin) sind wichtige Angriffsziele für Wirkstoffe. Ihre chemische Synthese und Faltung sind jedoch komplex, zeitraubend und nur in geringen Ausbeuten möglich. In ihrer Zuschrift (DOI: 10.1002/ange.201604733) beschreiben N. A. Patil, M. A. Hossain und Mitarbeiter eine neue Strategie, bei der z...
Article
Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time-consuming, and low yielding. Inspired by the cellular synthesis of pro-insulin in which the two constituent peptide chains are expressed as a single-chain precursor separated by a connecting C-peptide, we have develope...
Article
Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time-consuming, and low yielding. Inspired by the cellular synthesis of pro-insulin in which the two constituent peptide chains are expressed as a single-chain precursor separated by a connecting C-peptide, we have develope...
Article
Background and purpose: Insulin-like peptide 5 (INSL5) is a two-chain, three-disulphide bonded peptide of the insulin/relaxin superfamily, uniquely expressed in enteroendocrine L-cells of the colon. It is the cognate ligand of relaxin family peptide receptor 4 (RXFP4) that is mainly expressed in the colorectum and enteric nervous system. This stud...
Article
Full-text available
H2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood mechanism. The ectodomain of RXFP1 comprises an N-terminal LDLa module, essential for activation, tethered to a leucine-rich repeat (LRR) domain by a 32-residue linker. H2 relaxin is hypothesized to bind with high affinit...
Data
Supplementary Figures 1-7, Supplementary Tables 1-2.
Article
Full-text available
Insulin-like peptide 5 (INSL5) is an orexigenic peptide hormone belonging to the relaxin family of peptides. It is expressed primarily in the L-cells of the colon and has a postulated key role in regulating food intake. Its G protein-coupled receptor, RXFP4, is a potential drug target for treating obesity and anorexia. We studied the effect of modi...
Article
Full-text available
Human gene-2 relaxin (H2 relaxin) is a pleiotropic hormone with powerful vasodilatory and anti-fibrotic properties which has led to its clinical evaluation and provisional FDA approval as a treatment for acute heart failure. The diverse effects of H2 relaxin are mediated via its cognate G protein coupled-receptor (GPCR), Relaxin Family Peptide Rece...
Article
Insulin-like peptide 5 (INSL5) has recently been discovered as only the second orexigenic gut hormone after ghrelin. As we have previously reported, INSL5 is extremely difficult to assemble and oxidize into its two-chain three-disulfide structure. The focus of this study was to generate structure-activity relationships (SAR) of INSL5 and use it to...
Article
The mechanism of membrane disruption by melittin (MLT) of giant unilamellar vesicles (GUVs) and live cells was studied using fluorescence microscopy and two fluorescent synthetic analogues of MLT. The N-terminus of one of these was acylated with thiopropionic acid to enable labelling with maleimido-AlexaFluor 430 to study the interaction of MLT wit...
Article
Intramolecular acyl transfer equilibrium in peptides and proteins has stimulated the development of new methodologies for ligation, aggregation suppression or difficult peptide synthesis. Native chemical ligation or aggregation suppression methodologies are based on an X-to-N acyl transfer of a peptide chain (X = S, O). The reverse reaction from N-...
Article
Full-text available
Bioactive peptides play important roles in metabolic regulation and modulation and many are used as therapeutics. These peptides often possess disulfide bonds, which are important for their structure, function and stability. A systematic network of enzymes-a disulfide bond generating enzyme, a disulfide bond donor enzyme and a redox cofactor-that f...
Article
Insulin-like peptide 5 (INSL5) is a complex two-chain peptide hormone constrained by three disulfide bonds in a pattern identical to insulin. High expression of INSL5 in the colon suggests roles in activation of colon motility and appetite control. A more recent study indicates it may have significant roles in the regulation of insulin secretion an...

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Projects

Project (1)
Archived project
1. Optimization of chemical synthesis of INSL5 and other peptides. 2. Structure-function studies and new drug development based on insulin family peptides