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Accelerate Your DHODH Inhibitors (Orotomides) based Antifungal Drug Discovery & Development: CRO Service for Early-Stage Research

Invasive fungal infections (IFIs) represent a significant global health challenge, causing high mortality rates, particularly in immunocompromised patients. The emergence of antifungal resistance and the limited arsenal of available drugs necessitate the urgent discovery and development of novel therapeutic strategies. At Creative Biolabs, we are at the forefront of this critical fight, specializing in early-stage research and development services for DHODH inhibitors (orotomides) – a revolutionary class of antifungal agents. Request a quote

Understanding the Threat: The Unmet Need in Antifungal Drug Development

Fig.1 DHODH Inhibitors (Orotomides) antifungal drugs. (Creative Biolabs Authorized)

Despite advancements in medicine, fungal infections remain a formidable adversary. Traditional antifungal drugs often face limitations such as:

  • Narrow Spectrum of Activity: Many existing drugs are effective against only a limited range of fungal pathogens.
  • Toxicity and Side Effects: Some highly effective antifungals exhibit significant adverse effects, restricting their clinical use.
  • Emerging Resistance: Fungi are rapidly developing resistance to current therapies, rendering treatments ineffective and leading to treatment failures.
  • Limited Novel Mechanisms of Action: For decades, the antifungal drug pipeline has seen a scarcity of compounds with truly novel mechanisms, leading to cross-resistance issues.

The urgent need for new, effective, and well-tolerated antifungal agents with unique mechanisms of action is undeniable. This is where DHODH inhibitors, specifically the orotomides, offer a beacon of hope.

Our Comprehensive CRO Services for DHODH Inhibitor Drug Discovery

Target Services
Hit Identification
In Vitro Services
In Vivo Services

Target Identification & Validation

  • Fungal DHODH Expression & Purification: Recombinant production and purification of fungal DHODH enzymes from various pathogenic species.
  • Enzyme Kinetics & Inhibition Assays: Detailed characterization of compound potency against fungal DHODH, and selectivity assays against human DHODH.
  • Mechanism of Action Confirmation: Studies to confirm the specific binding site and inhibitory mechanism of your compounds using biochemical and biophysical techniques.

Compound Library Screening & Hit Identification

  • High-Throughput Screening (HTS): Screening of diverse chemical libraries against fungal DHODH targets to identify novel hit compounds.
  • Fragment-Based Drug Discovery (FBDD): Utilizing FBDD approaches to identify low-molecular-weight fragments that bind to DHODH, followed by fragment growing and linking.
  • Structure-Based Drug Design (SBDD): Leveraging computational chemistry and crystallography to design and optimize novel DHODH inhibitors based on the enzyme's 3D structure.
  • Medicinal Chemistry & Lead Optimization
    • Structure-Activity Relationship (SAR) Studies: Comprehensive SAR analysis to understand the relationship between chemical structure and biological activity.
    • Physicochemical Profiling: Measurement of solubility, cLogP, pKa, and other key physicochemical parameters.

In Vitro Biology & ADME/DMPK

  • In Vitro Antifungal Activity Assessment
    • Minimum Inhibitory Concentration (MIC) & Minimum Fungicidal Concentration (MFC) Determination: Evaluation of compound efficacy against a broad panel of clinically relevant fungal strains.
    • Time-Kill Assays: Assessment of the rate and extent of fungal killing over time.
    • Synergy Studies: Investigating potential synergistic effects of DHODH inhibitors with existing antifungal agents.
    • Fungal Permeability & Efflux Studies: Understanding compound uptake and efflux mechanisms in fungal cells.
    • Resistance Profiling: Studies to monitor the development of resistance to DHODH inhibitors in vitro.
  • In Vitro ADME
    • Metabolic Stability: Evaluation of metabolic stability in microsomes and hepatocytes (fungal and mammalian).
    • Plasma Protein Binding: Assessment of compound binding to plasma proteins.
    • Permeability Assays: Caco-2 and PAMPA assays to predict intestinal absorption.
  • In Vitro Cytotoxicity: Assessment of compound toxicity in various mammalian cell lines.

In Vivo Pharmacology Models

  • In Vivo Pharmacokinetics (PK)
    • Single-Dose PK Studies: Determination of pharmacokinetic parameters (Cmax, Tmax, AUC, half-life) in relevant animal models.
    • Bioavailability Studies: Assessment of oral bioavailability.
    • Tissue Distribution: Evaluation of compound distribution into target tissues.
  • Preliminary In Vivo Toxicity Studies: Short-term toxicity assessments in animal models to identify potential safety concerns.

Fig.2 Research on DHODH Inhibitors (Orotomides) Antifungal drugs. (Creative Biolabs Authorized)

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The Power of Orotomides: A Unique Mechanism of Action

Orotomides represent a groundbreaking class of antifungal drugs, distinguished by their novel mechanism of action (MoA): selective inhibition of fungal dihydroorotate dehydrogenase (DHODH). DHODH is a crucial enzyme in the de novo pyrimidine biosynthesis pathway. Pyrimidines (cytosine, thymine, and uracil) are essential building blocks for DNA and RNA, vital for cell growth, division, and overall survival. Unlike existing antifungal classes that target the fungal cell wall or membrane, orotomides precisely target fungal DHODH. This inhibition disrupts the de novo pyrimidine synthesis pathway, effectively starving the fungal cell of the necessary components for nucleic acid production. This leads to:

  • Fungicidal Activity: Rather than merely inhibiting growth, orotomides exhibit fungicidal activity against a broad range of pathogenic fungi, including Aspergillus species (e.g., A. fumigatus, A. terreus), Scedosporium prolificans, Lomentospora prolificans, and Fusarium species. This fungicidal action is a significant advantage over many fungistatic agents.
  • Fungal-Specific Targeting: Fungal DHODH differs structurally from human DHODH, allowing orotomides to selectively inhibit the fungal enzyme with minimal impact on host cells, thereby reducing the potential for host-related toxicity.
  • Reduced Resistance Potential: The novel mechanism of action means that fungi resistant to existing antifungal classes (e.g., azoles, echinocandins, polyenes) may remain susceptible to orotomides, offering a crucial treatment option for difficult-to-treat infections.

Why Choose Creative Biolabs for Your DHODH Inhibitor Program?

  • Specialized Expertise
  • State-of-the-Art Facilities
  • Integrated Solutions
  • Customizable Approach
  • Rapid Turnaround Times

Target Customer Groups

  • Pharmaceutical and Biotechnology Companies: Seeking to expand their antifungal pipeline with novel mechanisms.
  • Academic Research Institutions: Require specialized expertise and resources for their early-stage antifungal drug discovery projects.
  • Virtual Biotechs: Looking for a comprehensive, integrated solution for drug discovery without the overhead of in-house labs.
  • Grant-Funded Research Teams: Needing to outsource specific experiments or entire project phases to accelerate their progress.

Ready to Accelerate Your Antifungal Drug Discovery? Partner with Creative Biolabs to unlock the full potential of DHODH inhibitors in combating life-threatening fungal infections. Our expertise, advanced capabilities, and commitment to innovation will empower your research and accelerate your path to novel antifungal therapies. Contact us today to discuss your specific research needs and discover how our DHODH inhibitor services can benefit your program.

FAQs

What makes DHODH inhibitors a promising new class of antifungals?

DHODH inhibitors, orotomides, offer a unique fungicidal mechanism of action by disrupting pyrimidine biosynthesis, which is essential for fungal growth. Their fungal-specific targeting minimizes toxicity to human cells, and their novel mechanism provides a crucial alternative for treating drug-resistant fungal infections.

Which fungal pathogens are most susceptible to orotomides?

Orotomides have demonstrated excellent activity against a broad range of clinically significant mold infections, including Aspergillus species (especially A. fumigatus), Scedosporium, Lomentospora, and Fusarium. While some orotomides may have limited activity against Candida species, ongoing research is exploring broader-spectrum derivatives.

What stage of drug discovery do your services cover?

We specialize in early-stage research, from target identification and validation through hit identification, lead optimization, and preclinical candidate nomination. We provide the foundational data necessary for advancing compounds into later-stage preclinical and clinical development.
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