Monthly mycetoma meeting 2nd May 2023

[wwjvdsande]

MINUTES

Time: May 2nd (12 noon UK, 1pm EU, 11pm Aus) Timezones.

The Outlook invite can be found here

Location: https://uni-sydney.zoom.us/j/99281549497. In case of failure, use https://ucl.zoom.us/j/99789829423 and in case of double failure use MycetOS meeting teams link Chair: UCL Minute taker: EMC Previous meeting: [here]https://www.youtube.com/watch?v=IHdIp6un3Uc&feature=youtu.be) Recording: here Present: @dmitrij176 @fantasy121 @MA-Jjingyi @wwjvdsande @bebi78 @dosreic, Marita Emmanuel, Klementine Burrell-Sander, Alice Motion, Tariq Ayub Apologies: @mattodd

1) Series 1 SAR Gap compounds, actions from last meeting:

• [x] @fantasy121 to share SAR diagram shown in last meeting, clarifying that the known compounds are active. Then we select ca. 10 compounds to request from Epichem and @mattodd will email the finalised list to Epichem.

• [x] Paper: @dmitrij176 and @fantasy121 to finalise experimental section, including consistency of sig fig accuracy of data

• [x] @fantasy121 to upload offline copy of lab notebook to USYD respository and provide link that LINK to Repository Hung's LabArchives: https://doi.org/10.25910/CS81-G976

• [ ] @dmitrij176 to do the same (onto UCL repository).

• [ ] @dmitrij176 to upload his Biological supplemental data (not in Labarchives). An Excel sheet can be generated from our current Master List displaying all data on the fenarimols tested: Action on @MA-Jjingyi and @wwjvdsande. @wwjvdsande will make the Excel after @mattodd is gone through the manuscript to make sure that all compounds are in. Only the fenarimols will be in this spreadsheet

• [ ] @mattodd to review final version of manuscript. Please don't go through the manuscript till @mattodd is finished

The cut-off for in vivo data is end of larva season 2022: In vitro data will continue to be collected in 2023 (In vivo data 2023 season might be added to later revisions of manuscript but don’t wait for this before submission)

2) @wwjvdsande: New transcriptomic data in our galleria grain model showed that siderophores are produced. These siderophores might be used as a trojan horse to get molecules into the grain. Could we couple fenarimols to siderophores may be to get them in? The idea of the siderophores was of interest. @dmitrij176 would discuss with @mattodd if they would be able to take this on. Also Alice Motion would discuss this at USyd.

• [ ] @bebi78 added some literature on how this coupling could be performed. he would check with collaborators from York to see if there might be interest there as well
• [ ] @dmitrij176 and @mattodd to discuss the possibility of coupling fenarimols to siderophores
• [ ] Alice motion discuss in USyd if there is interest to couple siderophores to fenarimols.
• [ ] Check if there is also interest for other compound series, and the chemical feasibility

3) Series 2 Meeting between the chemistry team and the highschools took place. The schools now all have their own targets. Klementine mentioned that all schools have their target. She will will officially be the corresponding researcher for Breaking Good matters (High School and Undergrad synthesis) at USYD with MycetOS (Replacement for @kym834)

4) Series 5 Actions based on potencies observed for most recent compound batches_ - e.g. https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/82#issuecomment-1325150305 https://github.com/OpenSourceMycetoma/Series-1-Fenarimols/issues/82#issuecomment-1325150305 were selected because they resembled the benzimidazoles which showed potent in vivo efficacy. The oxazoles were validated in vitro against Madurella mycetomatis and appeared to be very potent. They will be tested against Falciformispora senegalensis too. This series will be evaluated in vivo in the new larval season. @dosreic mentioned that it is difficult for DNDi to obtain molecules from DNDi because of the MTAs. Alice Motion and Marita Emmanuel would see if they can access them as part of the project

Are there more oxazoles out there? Could check with DNDi. @bebi78 said: @AndreaOtago and @csuth22 were generating more compounds this year and would be happy to share (which is fantastic). @bebi78 send a new compounds ErasmusMC.

@fantasy121 to asked Peter and Alice Re: the students progress into the project. @fantasy121 to ask the two new Sydney Hons student to join Github, share their IDs and do the Scifinder lit search of the surrounding chemical space: are there other groups making similar compounds whom we could ask for donations? Response: Alice is working with Peiyan and Marita to progress their projects, they are currently planning their first posts and will officially join MycetOS at a later stage. Marita presented her synthesis plan for series 5

5) Series 6: ketoximes 19 compounds designed. Most of them are synthesized by UCL. The compounds still need to be tested at ErasmusMC. Will do as soon as possible. [ ] @dmitrij176 to share the figure of the compounds that have been shipped. There were some compounds which appeared to be different than designed. They are purified and will be shipped to Wendy for testing.

6) MMV Global Health Priority Box screened against Madurella mycetomatis and Falciformispora senegalensis. The data is uploaded in the spreadsheet.

7) Rohan’s contributed compounds: 96 well plate received.

8) Kinase inhibitor library. The updated KCGS library was ordered on 1st of May. Bio-informatical analyses have been carried out by Mickey. @bebi78 can send some 10 targets

9) Bioinformatics: Waleed requested information on which aspect of bioinformatics should be prioritised to work on first. @wwjvdsande corresponded offline with him. This will include a Phylogenetic tree to work out relationships of various species were identified as high priorities so that we can search the literature for closely related species to Mycetoma, and for the potential structures of the drug target, which would enable us to simulate our data/estimation/computational models

10) AOB Other Updates: USYD UCL Erasmus Other sites

Next meeting: May 23rd

[mattodd]

Thanks for posting the issue, @wwjvdsande, I made a few additions/tweaks. Hi all - I'm afraid I'm an apology for the meeting - I need to attend a teaching planning meeting at UCL. If @dmitrij176 is happy to chair, great, if not could someone else please step in? Not yet had a chance to finish reviewing the manuscript - I've started, though, so please (in an idea world...) make no changes till I say I'm done.

[fantasy121]

[fantasy121]

Here's the reduced list of suggested compounds (11 now, from 17)

Compounds suggested and reasoning:

_A’) Bridging compounds to link mind map target to lead MYOS_00003_0001 SCYX0001335912 SCYX0001322027

_B’) Modification of 3-Py (match pairing with lead MYOS00003 through bridging compounds SCYX0001335912) SCYX0001574838

C’) Di-substitution on both phenyl rings (match pairing with leads through bridging compounds SCYX0001322027) SCYX0001338488

D’) Removal of 4-substition (match pairing with leads through bridging compounds SCYX0001322027) SCYX0001336037 SCYX0001388141

_E’) Modification of 2-substitution (match pair with leads MYOS00008, serves as bridging to A’) SCYX0001294212 SCYX0001278548

_F’) 3-Substitution (close match to MYOS00002/8) SCYX0001315839

_G’) Modification of 3-Py (Match pair to MYOS00002) SCYX0001255546

_H’) Core modification –OH to –F (Match pair to MYOS00002) SCYX0001268121

Potent compounds being matchpaired with: MYOS_0003 IC50 0.6 MIC50 4.0, survival 6.65% MYOS_00008 IC50 1.3 MIC50 8.0 Survival 36.67%*** MYOS_00002 (X=Cl) IC50 0.2 MIC50 1.0 Survival 1.98%

[fantasy121]

I have also updated the mind map with potency.

[MA-Jjingyi]

02052023 MyctOS meeting -MA.pptx Hi all, I have also updated the MIC50 data in Spreadsheet. and the slides are here. if you have any doubt of this data, please leave me a message.

[bebi78]

@dosreic @wwjvdsande I could provide the new and active niclosamides for DMPK testing. Would 10 mg be enough for testing?

[wwjvdsande]

@dosreic @mattodd @dmitrij176 @fantasy121 May be the active fenarimols too? Some of them are from the epichem library. Also the three bendimazoles tested in vivo would be great fenbendazole, carbendazim and MMV1782387. I'm sure MMV would be willing to provide MMV1782387 too.

[dosreic]

Hi everyone! In theory, any compound could go. I’m not sure yet how many compounds we could send and how much compound they would need. Lauren is on annual leave and as soon as she comes back, I will let you know. In the meantime, we should make a list of the compounds that we would like to test and if they are available, where, and how much. Would you like to set up a conversation with Lauren as well? So she can introduce you and everyone to the assays and the idea?

Luiza Cruz, PhD I Drug Discovery Coordinator Drugs for Neglected Diseases initiative (DNDi) Rua São José 70 – Sala 601 - Centro | ZIP 20010020 Rio de Janeiro | Brazil M: +55 37 999072470 | @.**@.> dndi.org

[A picture containing text, clipart Description automatically generated]

De: Wendy van de Sande @.> Enviada em: segunda-feira, 8 de maio de 2023 11:08 Para: OpenSourceMycetoma/Monthly-zoom-meetings @.> Cc: Luiza Cruz @.>; Mention @.> Assunto: Re: [OpenSourceMycetoma/Monthly-zoom-meetings] Monthly mycetoma meeting 2nd May 2023 (Issue #5)

@dosreichttps://github.com/dosreic @mattoddhttps://github.com/mattodd @dmitrij176https://github.com/dmitrij176 @fantasy121https://github.com/fantasy121 May be the active fenarimols too? Some of them are from the epichem library. Also the three bendimazoles tested in vivo would be great fenbendazole, carbendazim and MMV1782387. I'm sure MMV would be willing to provide MMV1782387 too.

— Reply to this email directly, view it on GitHubhttps://github.com/OpenSourceMycetoma/Monthly-zoom-meetings/issues/5#issuecomment-1538423568, or unsubscribehttps://github.com/notifications/unsubscribe-auth/A4KDXHUBQO3T75TTVSJUKMTXFD45LANCNFSM6AAAAAAXRY3SRU. You are receiving this because you were mentioned.Message ID: @.***>

[bebi78]

@dosreic Testing will start in July as mentioned in your email? I'm not sure but maybe Andy Nortcliffe (Nottingham) also knows more about it (e.g., required amounts). We sent some samples to Dundee last autumn for the OSN P1Tc project he supervises. @wwjvdsande Maybe there is already data published and available for well-known antifungals such as fenbendazole and carbendazim?

[fantasy121]

@dosreic @mattodd @dmitrij176 @fantasy121 May be the active fenarimols too? Some of them are from the epichem library. Also the three bendimazoles tested in vivo would be great fenbendazole, carbendazim and MMV1782387. I'm sure MMV would be willing to provide MMV1782387 too.

Sounds good to me. For this testing, just to confirm, where would we source the fenarimols to send? Do you need more sample from me? Do you still have some stored at Erasmus? Are we asking from Epichem?

[fantasy121]

[fantasy121]

Above is the latest shipment of Fenarimols from USYD. This batch addresses some SAR gaps such as: modification of 3-pyridyl ring, and extension of 4- substitutions.

[bebi78]

@fantasy121 So Buchwald was successful?! @kym834 was asking for some suggestions to modify series 2 compounds in this way.

[mattodd]

@fantasy121 this is great, well done. I had envisaged the SAR gap list simply going to Epichem, with DNDi's blessing, for them to say whether they are willing to ship to Wendy on our behalf. As for the non-Epichem compounds, I'm not sure, but if someone could gather together a final list of compounds desired, that'd help clarify.

[memm0740]

My post on my honours project including research update and synthetic plan- https://github.com/OpenSourceMycetoma/series-5-benzimidazoles/issues/2#issuecomment-1558989625