Covid-19 Joint Venture Opportunity
Alcamena is looking for a partner to rapidly develop a pan-coronavirus antiviral peptidomimetic drug. The ideal partner would have clinical development, manufacturing, and marketing capabilities.
About us: Alcamena has developed a transformative high speed drug engineering platform. The backbone of our platform is a cutting edge, proprietary, Directed Evolution approach, that compresses millions of years of evolution into a few weeks. The technological advantages of our platform are innovative library designs and advanced screening and selection approaches (see AlcamenaBio.com). Our results have been independently validated in federal laboratories through jointly funded NIH projects (R43 NS105289; R43 NS110112). Through these projects, we have demonstrated that our technology can produce proteins with binding affinities exceeding that of most antibodies (low pM range), and/or have tissue permeability approaching that of small molecules that cross the lipid bilayer readily.
Proposed Drug: An orally bioavailable peptidomimetic inhibiter of the Covid-19 protease, M pro.
Proposed Target: Mpro: cuts the viral polypeptide into functional proteins1. This enzyme is not found in humans; therefore, our inhibitor should have a low risk of side effects.
Mechanism of Action: Inhibition of Mpro is predicted to alleviate coronavirus symptoms by preventing the formation of functional virus in the body.
Timelin:
Activity |
Step |
Time |
||
Peptide development |
Library construction and M pro expression | 1 month | 5 months | |
8 to 10 rounds of affinity selection | 2 months | |||
Next Generation Sequencing | 1 month | |||
Peptide synthesis | 1 month | |||
IND enabling |
1o Pharm |
Enzymatic activity screen (on & off target) Binding affinity |
1 month | 10 months |
Cellular activity screens | 3 months | |||
Transgenic mouse model assessment | 6 months | |||
General & Gene Tox; Safety Pharm |
Dose range finding studies in rat and monkey In vitro Ames and chromosome aberration assays hERG assay |
>2 months | 5 months | |
2-Week-toxicology and TK studies with safety pharmacology + 1 month recovery in rat and monkey | 3 months* | |||
*Because of the critical need for this drug, the FDA would allow initiation of clinical trials prior to release of the final study report. |
Total: 20 months |
Demonstrated Track-Record:
Alcamena recently developed a proprietary high affinity (130 pM) cell permeable phosphatase inhibitor (ALCA-71) with low nM cellular activity2, that has potent neurogenic and neuron survival affects3,4. ALCA-71 is a small orally bioavailable (3 kD) cyclic peptidomimetic. The inhibitor took under 6 months to develop and it is currently in the IND enabling study phase of development for traumatic brain injury, peripheral nerve injury, and chronic pain.
Why target Mpro?
- Protease inhibitors have proven to be effective against hard to treat viruses. They are a key component of the highly effective antiretroviral therapy (HAART) treatment for HIV5.
- An Mpro inhibitor would be effective against all coronavirus strains, including Covid-19.
Why Alcamena is best positioned company to develop a pan-coronavirus antiviral drug:
- Cutting-edge protein engineering platform independently validated in federal laboratories.
- Advanced gene library construction and screening approaches (see AlcamenaBio.com).
- Fast: genetic library construction and screening only takes a few weeks.
- Flexible: we can construct several different types of libraries and can use a wide variety of screening approaches (see AlcamenaBio.com) to select the optimal, natural, synthetic, and/or structured peptide.
- Highest gene library diversity (>1015) = high affinity, potency, and safety.
- Bioavailability: our structured cell penetrating peptides (CPP) have the highest activity in their class.
ALCA-71 Comparison to leading CPP technologies |
||||
Company |
Lead Drug |
Binding affinity (Kd) |
Intracellular activity (EC50) |
Ref. |
Alcamena |
ALCA-71 |
130 pM phosphatase |
250 nM |
2 |
Aileron |
ALRN-6924 |
34 nM MDM2; 83 nM MDMx |
5,000 – 10,000 nM |
6 |
Entrada |
ENTR-501 |
N/A |
5,000 nM |
7 |
- Stability: our libraries incorporate synthetic amino acids that are resistant to degradation.
- Safety: high affinity (pM) = low risk of off target effects.
Potential of our technology:
Our technology can be used as a fast response to any harmful agent in the future, for example new viruses, toxins, and poisons.
References:
- Jin, Z. et al. Structure of M(pro) from COVID-19 virus and discovery of its inhibitors. Nature, doi:10.1038/s41586-020-2223-y (2020).
- Nesti, E., Pisarchik, A. COMPOSITIONS AND METHODS FOR DEREPRESSING RE1 SILENCING TRANSCRIPTION FACTOR TARGET GENES. USA patent (2019).
- Nesti, E. Harnessing the master transcriptional repressor REST to reciprocally regulate neurogenesis. Neurogenesis 2, doi:10.1080/23262133.2015.1055419 (2015).
- Nesti, E., Corson, G. M., McCleskey, M., Oyer, J. A. & Mandel, G. C-terminal domain small phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation. Proc Natl Acad Sci U S A 111, E3929-3936, doi:1414770111 [pii]10.1073/pnas.1414770111 (2014).
- Riddler, S. A. et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 358, 2095-2106, doi:10.1056/NEJMoa074609 (2008).
- Carvajal, L. A. et al. Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia. Sci Transl Med 10, doi:10.1126/scitranslmed.aao3003 (2018).
- Song, J., Qian, Z., Sahni, A., Chen, K. & Pei, D. Cyclic Cell-Penetrating Peptides with Single Hydrophobic Groups. Chembiochem 20, 2085-2088, doi:10.1002/cbic.201900370 (2019).
Contact: Alex Pisarchik, Project Director, Ph. 650-307-4940; a.pisarchik@alcastem.com