Applied Sciences > Medicine > DG CY2020 8156 1

Research Title Anti-Pain and Anti- Neurodegeneration Drug Candidates: Discovery and Development (Year 2 of 3)
Research Personnel Leader:

Research Duration Start:
1 September 2019
1 September 2022
Research Location UPD-MSI
Research Description The DDHP-Marine Component Program seeks a second phase that will build on the accomplishments of the first phase to further advance marine drug discovery efforts in the country. In particular, the program will pursue further characterization and development of promising compounds discovered in Phase 1 and further develop the program's capability and infrastructure to undertake more efficient, effective, productive, and sustained drug discovery and development campaigns. By pursuing these goals, the program will be addressing the major challenges that typically hinder if not block progress in drug discovery and development programs. Among these is the fact, well known in the industry, that the number of compounds available for screening is a crucial limiting factor. The implication is that although the projects have already identified a number of promising compounds and will pursue their development, the chance of these compounds to move to clinical trials is statistically low as historically the progression of compounds through the drug discovery pipeline is characterized by very high attrition rates. Being a game of numbers, it is imperative for a drug discovery pipeline that a sufficiently large pool of novel compounds is available for screening. The high marine biodiversity available to researchers is a big advantage, but acquisition of compounds from these resources will need to be efficient and scaling up will be a necessity. The proposed program will deploy innovative solutions to this program. Developing an effective and efficient drug discovery enterprise is another important challenge. As a process, drug discovery is similar to other enterprise-scale, production-oriented operations: it works as a value chain. The creation of value is distributed over the entre chain, and a weak link can compromise the productivity of the entire chain, and a weak link can compromise the productivity of the entire enterprise. Value chains are modeled as systems composed of hierarchical subsystems. Subsystems are not just different from each other, they in fact represent distinct capabilities in the enterprise and specialize in efficiently delivering the required intermediates in the process. A productive and efficient value chain results from optimal operation not just of the component that produce the final product but of all its components. Thus, the program will further develop and strengthen its entire core value chain by ensuring that sub-systems needed for key processes are in place, and that the distinct capabilities required to effectively implement each stage of the drug discovery value chain are sufficiently developed.
Research Objectives Project 1 aims to characterize and develop anti-pain and antineurodegeneration priority compounds from Philippine concideans and to test their efficacy in electrophysiology, DRG neuroactivity assays and animal pain models. Specifically, it aims: 1). to further characterize the Structure, Activity and the ADMETox of the priority peptides a. to characterize and assess structure-activity relationship using ICMBA, DRG and Electrophysiology of isolated neuroactive peptides through synthesis of analogues of the priority peptides; b. to further purify and assess the bioactivity in ICMBA, and structure from other priority extracts, fractions and isolates from samples prioritized in PharmaSeas Phase1 and DDHP Phase 1; c. to optimize large scale synthesis of priority peptides from Phase 1 and Pharmaseas; d. to test priority peptides in animal models for pain and neurodegeneration; e. to assess in silico the peptide pharmacokinetic properties of the priority peptide leads; f. to evaluate Nephrotoxicity/Hepatotoxicity of priority peptide leads. 2). To characterize neuroactive leads from Phase 1 priority snail's species a. to assess semi-pure, pure native and synthetic peptides from Phase 1 priority snails for their specific neuroactive effects in mice using the intracranial mouse bioassay; b. to identify the ion channel/receptor targets of priority peptides using the existing eletrophysiology assay (two-electrode voltage clamp set-up); c. to expand the types of ion channels/receptors recombinantly expressed in frog oocytes to broaden coverage and discover new leads from Phase 1 priority species ; and d. to correlate biochemical data from purified peptides with transcriptome sequences to confirm the peptide sequence and discover other peptide sequences from the transcriptome library. 3). To develop a prototype transcriptomics-driven production system for bioactive Conus venom peptides (conopeptides) a. to increase the depth of coverage and average contig length (should cover 100% of putative precursor peptide sequence) of putative conopeptide-encoding transcript sequences and to generate proteomic data from venom of the same species to improve the quality and utility of previously developed transcriptomes necessary for reliable; b. to develop computational pipelines for general in silico structural and functional characterization of peptides predicted from transcriptomes, including prediction of their likely receptors; c. to develop a prototype recombinant expression system for production of conopeptides; d. to produce the identified priority conopeptides using the synthetic approach (inhouse or commercial) and/or the recombinant expression system (depending on the characteristics of the peptides); e. to compare the two (synthetic and recombinant) modes of peptide production based on key production parameters (including cost); f. to set up a screening system and facility for evalluating potential agonist/antagonist activities of conopeptides (synthetic or recombinant) against a panel of selected ion channels/receptors (expressed in human/mammalian cell lines) based on FRET-based detection of voltage-sensing chemical probes; g. to undertake preliminary experimental assays using the FRET-based screening system to establish preliminary bioactivity profiles of the conopeptides (synthetic or recombinant); and h. to compare the FRET-based screening system to the biological systems like electrophysiology.
Research Beneficiary(ies) 1) Medical benefits to patients; 2) Professional and economic benefits to medical doctors and health workers, hospitals and health clinics; 3) Economic benefits to Philippine Government (DOST), pharmaceutical companies, and entrepreneurs; 4) Academic institutions and researchers; 5) Local communities
Research Accoplishments [CY 2019] 1) 3 ISI publications and poster presentations across international and local conferences; 2) At least one patent on compound productions and/or application; 3) Data on in silico prediction of peptide pharmacokinetic properties (ADMET) for the 10 peptide leads; 4) Data on in vitro and in vivo ADMET properties for the 10 peptide leads; 5) One anti-pain peptide candidate tested in animal pain model; 6) Structure and target of 4 priority peptide of DDHP Phase 1 and Pharmaseas; 7) Large scale synthesis of three priority peptides; 8) Five (5) new pure bioactive conoidean peptide leads from Phase 1 Species; 9) Five (5) new synthetic bioactive (Chemically Synthesized) conoidean peptides); 10) Five (5) Conoidean species with transcriptome data; 11) Four (4) bioactive(Biosynthesized) conopeptides; 12) Conopeptides sequences (with inferred posttranslational modifications) predicted from the transcriptomes; 13) One (1) Computational pipeline (consisting of computational tools) for predicting PTMs and potential target receptors of conopeptides; 14) One (1) peptide drug delivery system; 15) Facility for FRET-based assays of conopeptide activity against candidate receptors/ion channel
Total Research Cost ₱1,497,946.80
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Code DG CY2020 8156 1
KRA Code
Priority Thrust DOST

Sector Applied Sciences
Actual Sector Medical science
Related sectors Chemistry
Entry revision: February 2021